Immunol Res DOI 10.1007/s12026-014-8533-0
IMMUNOLOGY AT THE UNIVERSITY OF IOWA
Effects of obesity on immune responses to renal tumors Vincent Chehval • Lyse A. Norian
Lyse A. Norian
Ó Springer Science+Business Media New York 2014
Abstract Kidney cancer incidence in the USA has been steadily increasing over the past several decades. The reasons for this are not completely clear, but an increased prevalence of known predisposing factors may be promoting this trend. Several major risk factors for kidney cancer have been identified. Among these, obesity is notable because its incidence has risen dramatically during this same period of time. Here, we will review the relationship between obesity and kidney cancer, and will explore the idea that obesity-mediated alterations in immune function may render immunotherapies for renal tumors ineffective. To support this idea, we will summarize characteristics of endogenous immune responses to renal tumors, as well as existing and developing immune-based therapies for kidney cancer patients. In doing so, we will highlight the ways in which altered immune function in obese individuals may render these therapies ineffective. Keywords
Obesity Kidney cancer Tumor immunity Immunotherapy
Kidney cancer: incidence and diagnosis Kidney cancer is one of the ten most common cancers in men and women in the USA. It can be broadly classified into three main types, depending on the location of the tumor and the age of the patient. Renal cell carcinoma (RCC) arises from the kidney parenchyma, which contains V. Chehval L. A. Norian (&) Department of Urology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA e-mail: [email protected] L. A. Norian Interdisciplinary Graduate Program in Immunology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA L. A. Norian Holden Comprehensive Cancer Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA L. A. Norian Fraternal Order of Eagles Diabetes Research Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
the nephrons or filtering units of the kidney. Renal transitional cell carcinoma (RTCC) arises from the renal pelvis and calyces, which act as the collecting system of the kidney. Both RCC and RTCC occur in adults, whereas Wilms tumors occur in children. This review will focus on RCC, as it is the most common type of kidney cancer, and by itself accounts for nearly 2–3 % of all malignant tumors in US adults [1, 2]. RCC is one of the most lethal urologic tumors, with approximately 30–40 % of patients ultimately dying from their cancer. In the USA, about 65,000 new cases are diagnosed and about 13,500 patients die annually from RCC. Men develop RCC more frequently than women, and the overall male-to-female ratio is roughly 2:1. RCC is rare in children and young adults; the highest rates of diagnosis occur when individuals are in their 60s and 70s [1]. There are several different histologic types of RCC, with the most common being clear cell RCC (70– 80 %), papillary RCC (10–15 %), and chromophobe RCC (3–5 %) [3]. Several other rare variants have also been described. Renal tumors often remain asymptomatic until they are quite large or until advanced disease develops, and because of this, diagnosis is frequently delayed. Contrasted
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computed tomography (CT) scans of the abdomen and renal ultrasounds are the most commonly used imaging modalities for the diagnosis of RCC. However, magnetic resonance imaging (MRI) scans and kidney X-rays with dye, referred to as intravenous pyelograms (IVP), may also be used. It is estimated that over half of all renal tumors are diagnosed incidentally on imaging studies that were ordered for other reasons [3]. Fortunately, many tumors diagnosed in this manner are confined to the kidney and are associated with improved survival. For such localized tumors, the 5-year survival rate is 45–85 %, depending on the tumor stage and location [4]. Symptoms associated with local renal tumor growth include: blood in the urine (microscopic and visible), flank pain, development of bleeding around the kidney, and a palpable flank mass. Once tumors metastasize, the prognosis becomes much worse, with 5-year survival rates of 0–10 % [5]. Symptoms associated with metastatic disease may include: persistent cough, bone pain, pathologic bone fractures, weight loss, malaise, and cervical lymph node enlargement. The treatment of choice for organ-confined RCC remains surgical excision via radical or partial nephrectomy. However, even when primary surgery is successful, nearly 20–30 % of patients with localized RCC will experience tumor recurrence, and this typically happens within 3 years of surgery [1, 3, 5]. Metastatic disease is notoriously refractory to radiation therapy and chemotherapy. Therefore, immunebased therapies are among the most promising options for these patients, along with other biologic approaches that include targeted molecular therapies and anti-angiogenesis therapies [3]. The incidence of RCC has been slowly increasing since 1970, and numerous studies have examined possible reasons for this trend [2, 6]. Although increased diagnosis due to improved imaging techniques is likely part of the explanation, there are indications that the rate of de novo RCC formation is also increasing. In a study published in 2008, Decastro et al. [7] examined the confounding factors of increased use of abdominal imaging studies, increased age of the population, and other factors as potential reasons for the higher diagnosis rates of RCC. The authors found that the incidence of RCC was increasing independently of these factors. Thus, RCC tumors were arising more frequently, suggesting that the prevalence of one or more known predisposing factors was also increasing.
Obesity as a major risk factor for RCC Several risk factors for the development of RCC have been identified, with tobacco use, hypertension, and obesity at the top of the list [2, 8]. Prolonged tobacco smoke exposure and tobacco use of any kind is one of the most widely
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accepted risk factors for RCC, with a relative risk of 1.4– 2.5 compared with controls, meaning that for every one non-smoker who developed RCC, 1.4–2.5 smokers developed RCC [2]. All forms of tobacco use are implicated as RCC risk factors in a dose-dependent manner. However, as tobacco use has been steadily declining over the past several decades, it seems unlikely that tobacco could be causing the observed increases in RCC incidence. Hypertension has also been implicated as an independent risk factor for RCC in women [2, 9] and has been linked to increased mortality from RCC in men [9]. It is estimated that as of 2013, one in three US adults has high blood pressure [10]. Thus, it is possible that the widespread prevalence of hypertension could be contributing to the increased rates of RCC. More recently, obesity has become accepted as a major risk factor for RCC. According to CDC data for 2013, nearly 36 % of US adults are obese and another 33 % are overweight [11–13]. Using this information and the increasing rate of obesity since the 1970s, Finkelstein et al. [14] estimated that by 2030, 51 % of the American population will be obese. Obesity is most commonly defined as a body mass index (BMI) over 30, but other measures of obesity such as the percentage of visceral adipose tissue or the diameter of the peri-nephric fat pad are being used with increasing frequency [8, 15–17]. Multiple studies have indicated that the increased incidence of RCC in Western countries can be partially attributed to local increases in obesity, with some reports suggesting that 40 % or more of RCC cases in the USA are causally linked to obesity [2, 18, 19]. As obesity is also a risk factor for developing hypertension [20], it is possible that obesity may promote the formation of renal tumors in multiple ways: via direct effects on tumorigenesis and tumor progression and via indirect effects on cardiovascular function. A number of other factors have been implicated in the development of RCC, including lead exposure, diet, and numerous chemical compounds, but no direct causal relationship has been established for these factors [2]. The positive association between obesity and kidney cancer is one of the strongest in the field of oncology, and numerous studies have provided evidence of this trend. A 2001 review article by Bergstrom et al. [21] identified 24 studies that had examined the relationship between obesity and RCC development in Western countries between 1966 and 1998. Their evaluation showed that 21 out of 24 studies found an increased incidence of RCC in both men and women with elevated BMIs compared to those with lower BMIs. The authors determined that each unit of increased BMI was associated with a relative risk of RCC development of 1.07 (95 % CI 1.05–1.09). Translated into practical terms, this means that for approximately every 3 kg of increased body weight, the risk of RCC is increased by about 7 %. Similarly, a 2006 study involving 362,552
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Swedish men, followed from 1971 until death or the end of 1999, found a positive association between obesity and several cancer types, including RCC. Specifically, a relative risk of 1.8 was found for RCC in obese patients (95 % CI 1.4–2.4). This study also noted that as BMI increased linearly, the relative risk of RCC increased [22]. Results from the UK million-woman study published in 2007 revealed a significant link between obesity and the development of RCC. This study evaluated 1,222,630 women aged 50–64 from 1996 to 2001 and found that a 10-unit increase in BMI was associated with relative risk of developing RCC =1.53 (95 % CI 1.27–1.84) [23]. Comparable trends were identified in a 2012 study by BeebeDimmer et al. [19] in which 1,214 RCC subjects and 1,234 control subjects were analyzed; results from this study showed that obesity in early adulthood or within a 5-year period of time prior to diagnosis significantly increased the risk of developing RCC for white adults. More recently, a 2014 assessment of 156,774 participants in the US Women’s Health Initiative confirmed that increasing BMI is a predictor for RCC development [9], and a 2014 metaanalysis of 21 prior reports found an overall relative risk for developing RCC of 1.77 in obese versus lean men and women [18]. The effect of obesity on RCC progression is much less clear. Several reports have examined whether obesity is associated with more aggressive renal tumors, and their conclusions have been contradictory. In one retrospective study of 186 patients with localized renal tumors of\7 cm, an increased percentage of visceral adipose tissue was found to be an independent predictor of high-grade cancer [24], and another study illustrated that overweight patients with RCC are younger at diagnosis than are lean RCC patients [25], suggesting earlier tumorigenesis and/or heightened aggressiveness of tumor outgrowth. However, a 2012 report from the Mayo Clinic Rochester found that obesity was associated with the presence of less aggressive renal tumors and increased overall 5-year survival rates after nephrectomy (81.7 % for obese, 76.9 % for overweight, and 62.3 % for lean adults) [26]. Similar findings were reached in a Japanese study of 117 RCC patients undergoing nephrectomy; patients with increased visceral adipose tissue had lower-grade tumors and increased overall survival compared to lean study subjects [15]. In contrast, other studies have found no change in cancerspecific survival between obese and normal-weight RCC study subjects after nephrectomy [27]. Thus, although many studies have solidified the relationship between obesity and RCC, the effect of obesity on tumor progression and cancer-specific survival remains unclear. Importantly, the causes of increased RCC risk in obese adults remain unclear. Here, we will explore the hypothesis that obesity-mediated immune dysfunctions contribute to
enhanced tumor progression and diminished responses to immune-based therapies, an idea that has not yet been tested clinically.
Endogenous immune responses to RCC RCC is an immunogenic tumor, meaning that the immune system recognizes RCC-derived tumor antigens as foreign, and several efforts are underway to use this knowledge to improve outcomes for patients. At this time, the effect of obesity on endogenous immune responses to RCC is not known, so we will focus on general information regarding immunity to RCC in human subject studies that likely comprise both lean and obese adults. To better understand endogenous immune responses to RCC, we and others have examined systemic and local leukocyte subpopulations in human subjects with RCC. We found that the peripheral blood (PB) of RCC subjects contained significantly higher percentages of CD8? T cells that expressed B and Tlymphocyte attenuator (BTLA), a known marker of T cell functional exhaustion. Furthermore, the frequencies of BTLA? CD8? T cells increased with advancing tumor stage (Wald et al. 2014 Urologic Oncology, in press). A 2007 study found that nearly 70 % of the tumor-infiltrating leukocytes in RCC study subjects were CD3? T cells and 43 % were CD8? T cells [28]. In contrast, the authors found relatively few regulatory T cells, NK cells, or B cells within tumor masses. A 2013 study on systemic T cell responses to RCC found that although elevated percentages of myeloid and plasmacytoid dendritic cells were present in the PB of RCC patients, increased percentages of regulatory T cells were also present [29]. This report also examined local immune responses within RCC tumor tissue and found that the frequency of regulatory T cells was even higher in tumors than in PB. One of the most comprehensive evaluations of tumor-infiltrating lymphocytes in RCC is a 2012 study by Wang et al. [30]. In this report, the authors examined matched PB and tumor samples from 8 primary and 8 metastatic renal tumors. Although the sample size was small, this evaluation showed that the PB contained much higher percentages of CD8? T cells expressing CD27 than did renal tumors (approximately 80 vs 42 %). As CD27 ligation promotes enhanced T cell activation, differentiation, and survival, this suggests that CD8? T cells within renal tumors are less able to mediate protective anti-tumor immunity [31, 32]. In addition, RCC tumor-infiltrating CD8? T cells had a predominantly effector memory phenotype (CD62L-CD45RO?), whereas most CD8? T cells in the PB had a naive (CD62L? CD45RO-) or central memory (CD62L?CD45RO?) phenotype. Finally, the authors provided evidence to suggest that clonal expansion
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of RCC tumor-antigen-specific T cells occurred locally within the tumor [30]. Other groups have identified tumorinduced T cell anergy as a contributor to RCC advancement [33]. Thus, although tumor-specific T cells are present systemically and locally within RCC tumors, even before administration of immunotherapy, they may not be able to optimally exert protective immunity. T cell-mediated clearance of renal tumors may be inhibited by extrinsic factors as well. A study published in 2013 evaluated 35 RCC tumor specimens and peripheral blood samples from patients that ultimately developed metastatic RCC. Ten of the patients had metastatic disease at the time of nephrectomy, fourteen patients developed metastatic disease within 5 years of nephrectomy, and eleven patients developed metastatic disease 5 years after nephrectomy. Evaluation of PB samples revealed that those patients with metastatic disease at presentation had a significantly higher neutrophil/lymphocyte ratio (NLR) compared to those that developed metastatic disease after diagnosis [34]. In this same study, the authors also evaluated renal tumor cells for mRNA encoding the pro-apoptotic protein Fas ligand (Fas-L) typically found on the surface of cytotoxic T lymphocytes. Fas-L typically stimulates the Fas receptor on tumor cells, thereby activating tumor cell apoptosis. The study by Sejima et al. demonstrated that 21 out of 35 renal cancers contained cells expressing Fas-L mRNA including 10/11 of those patients diagnosed with metastatic disease, 9/14 of those diagnosed with metastatic disease within 5 years, and only 2/10 of those diagnosed with metastatic disease more than 5 years after nephrectomy, suggesting that the tumor cells were able to induce cytotoxic T cell apoptosis. The implication is that lower NLR ratios and lower Fas-L expression by tumor cells suggest stronger host immunity and slowed cancer progression [34]. Neutrophil accumulations have also been identified in late-stage RCC tumors by Minarik et al. [29], and higher levels of tumor-infiltrating neutrophils in RCC specimens have been associated with faster tumor recurrence and decreased overall survival [35]. As neutrophils are phenotypically similar to myeloid-derived suppressor cells (MDSCs), an immature cell population known to accumulate in cancer patients that inhibits T cellmediated anti-tumor activity, it is possible that ‘‘neutrophils’’ in such studies were actually MDSCs, thereby explaining why patients with lower NLR ratios had improved outcomes. MDSCs are known to impair T cell responses to RCC. We and others have found increased percentages of MDSCs in the PB and tumor masses of patients with RCC (Wald et al. 2014 Urologic Oncology, in press) and [33, 36, 37]. MDSCs inhibit T cell proliferation and decrease cytokine production through a variety of mechanisms, including local depletion of L-arginine supplies [38–41].
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Depleted local arginine levels decrease T cell proliferation, inhibit cytokine production, and decrease expression of the T cell antigen receptor CD3f [42]. In their 2005 paper, Zea et al. examined peripheral blood mononuclear cells (PBMCs) from 123 patients with metastatic RCC and compared them to PBMCs of cancer-free controls. The authors found that CD11b?CD14-CD15? MDSCs from patients with metastatic RCC displayed high levels of arginase activity, and depletion of these cells led to significant increases in T cell CD3f expression and IFNc production. These results again suggest that RCC leads to an environment of immunosuppression that is partially mediated by MDSCs. Along these same lines, a study that reviewed pathology slides from 306 patients with clear cell RCC found that increased tumor infiltration of mononuclear cells was associated with a twofold increase in allcause death and twofold increase in death from RCC [43]. Therefore, even though RCC incites protective T cell responses, the anti-tumor functions of effector cells generated will likely be blocked by MDSCs and/or other immunosuppressive leukocyte populations.
Current and future immunotherapies for RCC Taking the above information into account, current therapy for metastatic renal cell carcinoma is focused on immunebased therapies, targeted molecular therapies, and antiangiogenesis therapies. When disease is confined to the kidney, surgical excision is the treatment of choice. There is also evidence that patients with a solitary metastatic lesion or a limited number of resectable metastatic lesions benefit from surgical excision of those lesions. This concept holds true whether the lesions were discovered at the same time as the primary tumor or whether the lesions were discovered during surveillance after nephrectomy [44, 45]. Despite this, once metastatic disease is discovered, the average survival time is \1 year [46]. Even with this poor statistic, a survival advantage is seen in select patients with unrespectable metastatic disease who undergo removal of the primary renal tumor prior to receiving systemic therapy [47]. There are even isolated reports of spontaneous regression of metastatic lesions after removal of the primary tumor, but this is rare. Immunotherapies were some of the first systemic therapies to be developed for metastatic RCC. Interleukin-2 (IL-2) and IFN-a are the two most studied therapies. IL-2 therapy is postulated to mediate its anti-tumorigenic effects via activation of NK cells and effector T cells, but the exact mechanism of functioning in RCC remains unknown [46]. IFN-a is normally produced by lymphocytes and macrophages and initiates many downstream effects including enhanced antigen presentation and immunomodulation
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[46]. In a meta-analysis published in 2007, Hotte et al. [48] found that treatment regimens containing IL-2 were superior to regimens that did not contain IL-2. However, the results were modest, showing that IL-2 provided an increased response rate (measured via radiologic evidence of decreased tumor size) but no statistically significant survival advantage at 1 year. That being said, studies by the Rosenberg group at NCI have shown a 20 % objective response rate to high-dose IL-2 in patients with metastatic RCC; 9 % of treated patients showed complete and durable remission [49]. High-dose IL-2 has shown slightly improved response and cure rates when compared to standard dose IL-2 but is associated with substantial adverse side effects [50]. High-dose IL-2 is currently the only treatment that has shown the ability to cure metastatic RCC; however, the toxicity profile requires that it be reserved for patients with fewer medical problems and good performance status [50]. Many developing treatments for metastatic RCC are focused on immune-stimulatory therapies. Several vaccines are currently being tested, including IMA901. This vaccine was developed by comparing the mRNA expression profiles of RCC tumors to that of normal renal tissue. This process identified nine HLA-1 tumor- and one HLA-2 tumor-associated peptides (TUMAPs) that were highly overexpressed in cancerous tissue. The TUMAPs were then included in a vaccine which, when administered with a single dose of cyclophosphamide, was associated with longer overall survival, as compared to controls, in a recent Phase II trial [51]. Other vaccine trials currently underway involve AGS-003, which is a vaccine based on dendritic cells that is co-administered with the tyrosine kinase inhibitor, sunitinib. Preliminary results have shown improved overall progression-free survival with a low side effect profile. As sunitinib has been shown to decrease MDSC populations in RCC patients [52], it is possible that its inclusion here may be benefiting patients in multiple ways. Further trials of this approach are underway [53]. The promising results obtained in these vaccination studies reinforce the idea that boosting protective immunity can provide durable responses against advanced RCC. Other developing immune therapies for RCC focus on modulation of T cell functional status. Programmed Death 1 (PD1) is a cell surface receptor expressed by exhausted T cells. When T cells expressing this receptor come into contact with cells expressing the ligands (PD-L1 or PD-L2) for this receptor, the T cell response is downregulated [54]. It has been shown that patients with PD1-positive T cells tend to have larger tumors with an increased risk of metastasis and increased risk of cancer-specific death [54, 55]. As of 2014, several clinical trials using anti-PD-1 antibodies or anti-PDL1 antibodies are underway [54, 56– 58]. The rationale for these approaches is that blockade of
PD-1/PD-1 ligand interactions should prevent negative signals that initiate T cell exhaustion, thereby amplifying endogenous T cell responses to RCC. A preliminary study of 33 patients with advanced RCC published in 2012 showed a 27 % response rate to the therapy with a moderate side effect profile that would likely not preclude its use [56]. Other T cell therapies include antibodies to CTLA-4, an inhibitory T cell receptor associated with immunotolerance. Binding of CTLA-4 to its ligands B7.1 and B7.2 blunts ongoing T cell effector responses [59]. Ipilimumab is an anti-CTLA-4 antibody that is FDAapproved for use in melanoma and is being examined for use in RCC patients. One drawback to ipilimumab use is that it can produce serious side effects, including significant autoimmune events, in a minority of patients [60]. New studies combining ipilimumab with antibodies against PD-1 and/or PDL1 are underway, but effects of such combinatorial therapies in RCC are not yet known.
Obesity diminishes protective immune responses: effects on immunity to RCC? Given the fact that immunotherapies are being actively used and developed for the treatment of RCC, it is critical to understand how obesity might alter the efficacy of these therapies. There are numerous health concerns associated with obesity, including extensive detriments to the immune system. Obesity has been associated with a state of chronic inflammation characterized by elevated serum concentrations of the pro-inflammatory proteins C-reactive protein (CRP), IL-6, and TNF-a [61–63]. As chronic inflammation is known to inhibit protective immunity mediated by CD4? and CD8? T cells [39, 64, 65], it is not surprising that in humans, obesity is associated with decreased T and B cell proliferation, alterations in overall leukocyte counts, diminished production of antibodies after vaccinations, higher infection rates, and poor wound healing (reviewed in [66, 67] ). Specifically, reports have indicated that obesity is associated with increased total numbers of circulating CD3? T cells, primarily due to increased numbers of the CD4? subset accompanied by decreased numbers of CD8? T cells [68]. In this study, the subset composition of CD4? T cells was not examined, so it is not known whether the increased cells were effectors or regulatory T cells. Despite increases in total numbers, several studies have demonstrated that T cell function is compromised, as evidenced by decreased responses to mitogen stimulation [68– 70]. All of these factors suggest notable alterations to the immune system overall, and T cell immunity in particular, in obese individuals. Decreased T cell responsiveness would likely impair the efficacy of many immunotherapies currently being used or developed for RCC, such as high-
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Fig. 1 Mechanisms of obesity-mediated dysfunction in anti-tumor immunity: Obesity impacts protective immune responses in multiple ways. (1) Obesity is characterized by a state of chronic, systemic inflammation that is thought to originate from altered adipokine and cytokine secretion in white adipose tissue. Increased leptin and IL-6, and decreased adiponectin promote a systemic, pro-inflammatory host environment. (2) Obesity in mice has been linked to decreased dendritic cell (depicted in blue) entry into lymph nodes and a reduced ability of dendritic cells to stimulate the expansion of naive T cells. (3) T cells (depicted in gray) from obese mice and humans have diminished proliferative capacities, resulting in fewer effector T cells being generated. (4) Effector T cells that are produced may be more prone to exhaustion; high levels of PD-1 and BTLA have been found on CD8? T cells from RCC patients, but it is not clear whether these levels are further altered by obesity. (5) RCC tumors contain inhibitory MDSCs (depicted in red), and preliminary data suggest that local MDSCs’ prevalence is increased with obesity. Cumulatively, these factors would result in a more immunosuppressive, protumorigenic environment that would be refractory to immune-based therapies, an idea that has yet to be examined clinically
dose IL-2, vaccination therapies, anti-CTLA4, and antiPD1 or PD-L1 that rely upon T cell stimulation to mediate tumor clearance. Presently, direct support of this idea is not available from human studies. To date, much of the research examining the effects of obesity on immune function has been performed in mice and rats with genetic- or diet-induced obesity, and alterations in multiple cell types have been described. For example, several studies have shown that diet-induced obesity results in decreased frequencies of NK cells with reduced effector function [71, 72]. As NK cells can contribute substantially to tumor clearance even when present at low numbers, a loss in this cell population would promote accelerated tumor outgrowth. Other leukocyte populations are also impacted by obesity. We found that dietinduced obese mice had increased percentages of conventional DC in the spleen, but that these DC had a significantly decreased ability to induce CD8? T cell proliferation (Fig. 1) [73]. Our findings are in agreement with prior studies that had used bulk antigen-presenting cells from obese mice and found them to have a reduced
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ability to stimulate naive T cells [74, 75]. Phenotypically, we found no detectable alterations in splenic DC from lean and obese mice, so the cause of decreased stimulatory capacity in DC from obese mice remains unclear. Weitman et al. [76] recently reported that diet-induced obese mice have diminished fluid transport in lymphatic vessels, fewer lymphatic vessels, and decreased migration of DC and T cells into lymph nodes. These findings, when combined with our observations on the loss of DC function in obese mice, provide a compelling explanation for the reduced T cell responses [77] observed in obese rodents. In addition, others have shown that T cells from obese mice and rats have decreased proliferative responses to mitogen stimulation (Fig. 1) [78, 79], suggesting that T cell proliferative defects may be due to both extrinsic and intrinsic factors. In the context of anti-tumor immunity in response to immunotherapies, such changes in DC and T cell function would again be predicted to result in fewer endogenous, tumor-antigen-specific T cells becoming activated. Therefore, therapies such as tumor-antigen vaccines, antiCTLA4, and anti-PD-1, all of which rely upon effector T cell function, would likely show diminished efficacy in the clinic. An alternate source of immune modulation in obese individuals may stem from adipose tissue, rather than traditional primary or secondary immune organs. Leptin is a bioactive molecule secreted by adipocytes. It is structurally similar to IL-6 and can modulate activation of NK cells, production of pro-inflammatory cytokines, and stimulation of monocyte proliferation [80]. In animal models, the absence of leptin or leptin receptors has been associated with severe immune dysfunction, in addition to robust obesity. It has been shown that in obese individuals, circulating leptin levels increase, which in turn leads to a blunted central response to this molecule. Consequently, elevated circulating levels of leptin and activation of proinflammatory cells ensue [80, 81]. Adiponectin is another adipokine produced by fat cells, and its main function is as an anti-inflammatory molecule. Interestingly, in obese individuals, adiponectin levels are decreased, which further promotes systemic inflammation [11, 81]. The exact role these two molecules play in tumorigenesis is not yet fully understood; however, adiponectin levels have been shown to be reduced in patients with metastatic RCC and to correlate inversely with tumor size [82]. Other proposed mechanisms for the pro-inflammatory environment seen in obese individuals include increased fatty acid production, which directly stimulates TNF-a and IL-6 production from adipocytes, and adipose tissue growth outstretching its vascular supply leading to hypoxia, cell death, and inflammation [83, 84]. The interplay of all these factors is complex, and their net effects on immune function are not fully understood. However, it is clear that obesity is a pro-
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inflammatory condition with numerous adverse effects on cell-mediated immunity. How then does obesity impact immune responses to RCC, in the presence or absence of immune-based therapies? We have begun to examine this question using normal-weight mice and diet-induced obese mice with orthotopic RCC. We surgically implanted the syngenic renal tumor line Renca into age-matched lean and obese BALB/c mice [73]. We found that obese mice had profound alterations in their serum cytokine/chemokine profile, as marked by upregulation of 15 different proteins, including IL-1a, IL-7, IL-13, IL-17, and IP-10. Following tumor challenge, obese mice had a transient increase in renal tumor burden at day 7 post-tumor challenge, but this difference was not present at later time points. Upon examining tumor-bearing kidneys from obese mice, we found increased percentages of CD11b? DC. Instead of stimulating CD8? T cell expansion, these renal DC acted as regulatory cells [85] to inhibit T cell proliferation. To evaluate the effects of obesity on RCC treatment, we administered a DC- and T cell-dependent immunotherapy [86] at day 7 after tumor challenge. This therapy induced tumor regression in lean mice, and 80 % of treated lean mice cleared their tumors and survived through day 70. In contrast, the same therapy was not effective in obese mice; progressive tumor outgrowth was observed, and 100 % of obese mice succumbed to their renal tumors. Evaluation of renal tumors in the obese mice again revealed an increased percentage of regulatory DCs and decreased percentages of IFNc-producing CD8? T cells [73]. In addition, we have found that renal tumors and spleens from obese mice have increased percentages of MDSCs, with significant increases present by day 14 after tumor challenge; although the suppressive capacity of these cells is unchanged on a percell basis, the greater number of MDSCs in renal tumors and spleens would act to block protective T cell immunity (unpublished results). Our results, when combined with findings from other groups using obese tumor-free mice, suggest that obesity not only causes immune dysfunction, but also impairs protective responses to immune-based therapies for RCC (Fig. 1). It remains to be seen whether obese RCC patients have a similar loss of immunotherapeutic efficacy.
Summary RCC is a prevalent disease with an unfortunate propensity to metastasize. Obesity is a major predisposing factor for developing RCC, but the causes for this association remain unclear. RCC is one of the most immunogenic tumors known, and endogenous anti-tumor immune responses can be enhanced through the use of targeted immunotherapies.
Although immune-based therapies for advanced RCC have shown promise in a subset of patients, significantly more work is needed to achieve objective responses in a majority of treated individuals. For this reason, new immune-based treatments for RCC are actively being explored. However, given the facts that obesity is concurrently rising at an alarming rate and that obesity is known to impair normal immune function, it is possible that any new immunotherapy for metastatic RCC will have reduced efficacy in obese patients. Moving forward, immune-based therapies (vaccines and T cell modulators) appear to be at the forefront of treatment options for advanced RCC. It is unknown whether their effectiveness will be durable in the coming years as obesity continues to increase. Acknowledgments This work was supported by a National Cancer Institute Grant (# 1 R01 CA181088-01) to LAN.
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University of Iowa Immunology 2014 15. Naya Y, Zenbutsu S, Araki K, Nakamura K, Kobayashi M, Kamijima S, Imamoto T, Nihei N, Suzuki H, Ichikawa T, et al. Influence of visceral obesity on oncologic outcome in patients with renal cell carcinoma. Urol Int. 2010;85:30–6. 16. Clark W, Siegel EM, Chen YA, Zhao X, Parsons CM, Hernandez JM, Weber J, Thareja S, Choi J, Shibata D. Quantitative measures of visceral adiposity and body mass index in predicting rectal cancer outcomes after neoadjuvant chemoradiation. J Am Coll Surg. 2013;216:1070–81. 17. Ahima RS, Lazar MA. Physiology: the health risk of obesity– better metrics imperative. Science. 2013;341:856–8. 18. Wang F, Xu Y. Body mass index and risk of renal cell cancer: a dose–response meta-analysis of published cohort studies. Int J Cancer. 2014. doi:10.1002/ijc.28813. 19. Beebe-Dimmer JL, Colt JS, Ruterbusch JJ, Keele GR, Purdue MP, Wacholder S, Graubard BI, Davis F, Chow WH, Schwartz KL. Body mass index and renal cell cancer: the influence of race and sex. Epidemiology. 2012;23:821–8. 20. Ostchega Y, Hughes JP, Terry A, Fakhouri TH, Miller I. Abdominal obesity, body mass index, and hypertension in US adults: NHANES 2007–2010. Am J Hypertens. 2012;25:1271–8. 21. Bergstrom A, Hsieh CC, Lindblad P, Lu CM, Cook NR, Wolk A. Obesity and renal cell cancer: a quantitative review. Br J Cancer. 2001;85:984–90. 22. Samanic C, Chow WH, Gridley G, Jarvholm B, Fraumeni JF Jr. Relation of body mass index to cancer risk in 362,552 Swedish men. Cancer Causes Control. 2006;17:901–9. 23. Reeves GK, Pirie K, Beral V, Green J, Spencer E, Bull D. Cancer incidence and mortality in relation to body mass index in the million women study: cohort study. BMJ. 2007;335:1134. 24. Zhu Y, Wang HK, Zhang HL, Yao XD, Zhang SL, Dai B, Shen YJ, Liu XH, Zhou LP, Ye DW. Visceral obesity and risk of high grade disease in clinical t1a renal cell carcinoma. J Urol. 2013;189:447–53. 25. Waalkes S, Merseburger AS, Kramer MW, Herrmann TR, Wegener G, Rustemeier J, Hofmann R, Schrader M, Kuczyk MA, Schrader AJ. Obesity is associated with improved survival in patients with organ-confined clear-cell kidney cancer. Cancer Causes Control. 2010;21:1905–10. 26. Parker AS, Lohse CM, Cheville JC, Thiel DD, Leibovich BC, Blute ML. Greater body mass index is associated with better pathologic features and improved outcome among patients treated surgically for clear cell renal cell carcinoma. Urology. 2006;68:741–6. 27. Pfitzenmaier J, Pritsch M, Haferkamp A, Jakobi H, Fritsch F, Gilfrich C, Djakovic N, Buse S, Pahernik S, Hohenfellner M. Is the body mass index a predictor of adverse outcome in prostate cancer after radical prostatectomy in a mid-European study population? BJU Int. 2009;103:877–82. 28. Kopecky O, Lukesova S, Vroblova V, Vokurkova D, Moravek P, Safranek H, Hlavkova D, Soucek P. Phenotype analysis of tumour-infiltrating lymphocytes and lymphocytes in peripheral blood in patients with renal carcinoma. Acta Medica (Hradec Kralove). 2007;50:207–12. 29. Minarik I, Lastovicka J, Budinsky V, Kayserova J, Spisek R, Jarolim L, Fialova A, Babjuk M, Bartunkova J. Regulatory T cells, dendritic cells and neutrophils in patients with renal cell carcinoma. Immunol Lett. 2013;152:144–50. 30. Wang QJ, Hanada K, Robbins PF, Li YF, Yang JC. Distinctive features of the differentiated phenotype and infiltration of tumorreactive lymphocytes in clear cell renal cell carcinoma. Cancer Res. 2012;72:6119–29. 31. Hendriks J, Gravestein LA, Tesselaar K, van Lier RA, Schumacher TN, Borst J. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol. 2000;1:433–40. 32. Xiao Y, Hendriks J, Langerak P, Jacobs H, Borst J. CD27 is acquired by primed B cells at the centroblast stage and promotes germinal center formation. J Immunol. 2004;172:7432–41.
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33. Zea AH, Rodriguez PC, Atkins MB, Hernandez C, Signoretti S, Zabaleta J, McDermott D, Quiceno D, Youmans A, O’Neill A, et al. Arginase-producing myeloid suppressor cells in renal cell carcinoma patients: a mechanism of tumor evasion. Cancer Res. 2005;65:3044–8. 34. Sejima T, Iwamoto H, Morizane S, Hinata N, Yao A, Isoyama T, Saito M, Takenaka A. The significant immunological characteristics of peripheral blood neutrophil-to-lymphocyte ratio and Fas ligand expression incidence in nephrectomized tumor in late recurrence from renal cell carcinoma. Urol Oncol. 2013;31:1343– 9. 35. Jensen HK, Donskov F, Marcussen N, Nordsmark M, Lundbeck F, von der Maase H. Presence of intratumoral neutrophils is an independent prognostic factor in localized renal cell carcinoma. J Clin Oncol. 2009;27:4709–17. 36. Ochoa AC, Zea AH, Hernandez C, Rodriguez PC. Arginase, prostaglandins, and myeloid-derived suppressor cells in renal cell carcinoma. Clin Cancer Res. 2007;13:721s–6s. 37. Finke JH, Rayman PA, Ko JS, Bradley JM, Gendler SJ, Cohen PA. Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J. 2013;19:353–64. 38. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9:162– 74. 39. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S. Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol. 2006;176:284–90. 40. Ostrand-Rosenberg S, Sinha P. Myeloid-derived suppressor cells: linking inflammation and cancer. J Immunol. 2009;182:4499– 506. 41. Serafini P, Borrello I, Bronte V. Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression. Semin Cancer Biol. 2006;16:53–65. 42. Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, Delgado A, Correa P, Brayer J, Sotomayor EM, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigenspecific T-cell responses. Cancer Res. 2004;64:5839–49. 43. Webster WS, Lohse CM, Thompson RH, Dong H, Frigola X, Dicks DL, Sengupta S, Frank I, Leibovich BC, Blute ML, et al. Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival. Cancer. 2006;107:46–53. 44. Thyavihally YB, Mahantshetty U, Chamarajanagar RS, Raibhattanavar SG, Tongaonkar HB. Management of renal cell carcinoma with solitary metastasis. World J Surg Oncol. 2005;3:48. 45. Fottner A, Szalantzy M, Wirthmann L, Stahler M, Baur-Melnyk A, Jansson V, Durr HR. Bone metastases from renal cell carcinoma: patient survival after surgical treatment. BMC Musculoskelet Disord. 2010;11:145. 46. Ather MH, Masood N, Siddiqui T. Current management of advanced and metastatic renal cell carcinoma. Urol J. 2010;7:1–9. 47. Pantuck AJ, Belldegrun AS, Figlin RA. Cytoreductive nephrectomy for metastatic renal cell carcinoma: is it still imperative in the era of targeted therapy? Clin Cancer Res. 2007;13:693s–6s. 48. Hotte S, Waldron T, Canil C, Winquist E. Interleukin-2 in the treatment of unrespectable or metastatic renal cell cancer: a systematic review and practice guideline. Can Urol Assoc J. 2007;1:27–38. 49. Rosenberg SA. Interleukin 2 for patients with renal cancer. Nat Clin Pract Oncol. 2007;4:497. 50. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–41.
University of Iowa Immunology 2014 51. Walter S, Weinschenk T, Stenzl A, Zdrojowy R, Pluzanska A, Szczylik C, Staehler M, Brugger W, Dietrich PY, Mendrzyk R, et al. Multipeptide immune response to cancer vaccine IMA901 after single–dose cyclophosphamide associates with longer patient survival. Nat Med. 2012;18:1254–61. 52. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15:2148–57. 53. Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol. 2012;23(Suppl 8):35–40. 54. Inman BA, Harrison MR, George DJ. Novel immunotherapeutic strategies in development for renal cell carcinoma. Eur Urol. 2013;63:881–9. 55. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, Kwon ED. PD-1 is expressed by tumorinfiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13:1757–61. 56. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443– 54. 57. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, et al. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28:3167–75. 58. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366:2455–65. 59. Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565–94. 60. Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30:825–30. 61. Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL6. Diabetes Res Clin Pract. 2005;69:29–35. 62. Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer. 2004;4:579–91. 63. Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. 2007;56:1010–3. 64. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumorpromoting chronic inflammation: a magic bullet? Science. 2013;339:286–91. 65. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99. 66. Karlsson EA, Beck MA. The burden of obesity on infectious disease. Exp Biol Med (Maywood). 2010;235:1412–24. 67. Hance KW, Rogers CJ, Hursting SD, Greiner JW. Combination of physical activity, nutrition, or other metabolic factors and vaccine response. Front Biosci. 2007;12:4997–5029. 68. O’Rourke RW, Kay T, Scholz MH, Diggs B, Jobe BA, Lewinsohn DM, Bakke AC. Alterations in T-cell subset frequency in peripheral blood in obesity. Obes Surg. 2005;15:1463–8.
69. Tanaka S, Inoue S, Isoda F, Waseda M, Ishihara M, Yamakawa T, Sugiyama A, Takamura Y, Okuda K. Impaired immunity in obesity: suppressed but reversible lymphocyte responsiveness. Int J Obes Relat Metab Disord. 1993;17:631–6. 70. Nieman DC, Henson DA, Nehlsen-Cannarella SL, Ekkens M, Utter AC, Butterworth DE, Fagoaga OR. Influence of obesity on immune function. J Am Diet Assoc. 1999;99:294–9. 71. Smith AG, Sheridan PA, Harp JB, Beck MA. Diet-induced obese mice have increased mortality and altered immune responses when infected with influenza virus. J Nutr. 2007;137:1236–43. 72. Lautenbach A, Wrann CD, Jacobs R, Muller G, Brabant G, Nave H. Altered phenotype of NK cells from obese rats can be normalized by transfer into lean animals. Obesity (Silver Spring). 2009;17:1848–55. 73. James BR, Tomanek-Chalkley A, Askeland EJ, Kucaba T, Griffith TS, Norian LA. Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth. J Immunol. 2012;189:1311–21. 74. Smith AG, Sheridan PA, Tseng RJ, Sheridan JF, Beck MA. Selective impairment in dendritic cell function and altered antigen-specific CD8? T-cell responses in diet-induced obese mice infected with influenza virus. Immunology. 2009;126:268–79. 75. Macia L, Delacre M, Abboud G, Ouk TS, Delanoye A, Verwaerde C, Saule P, Wolowczuk I. Impairment of dendritic cell functionality and steady-state number in obese mice. J Immunol. 2006;177:5997–6006. 76. Weitman ES, Aschen SZ, Farias-Eisner G, Albano N, Cuzzone DA, Ghanta S, Zampell JC, Thorek D, Mehrara BJ. Obesity impairs lymphatic fluid transport and dendritic cell migration to lymph nodes. PLoS One. 2013;8:e70703. 77. Karlsson EA, Sheridan PA, Beck MA. Diet-induced obesity impairs the T cell memory response to influenza virus infection. J Immunol. 2010;184:3127–33. 78. Lamas O, Marti A, Martinez JA. Obesity and immunocompetence. Eur J Clin Nutr. 2002;56(Suppl 3):S42–5. 79. Sato Mito N, Suzui M, Yoshino H, Kaburagi T, Sato K. Long term effects of high fat and sucrose diets on obesity and lymphocyte proliferation in mice. J Nutr Health Aging. 2009;13:602–6. 80. Fernandez-Riejos P, Najib S, Santos-Alvarez J, Martin-Romero C, Perez-Perez A, Gonzalez-Yanes C, Sanchez-Margalet V. Role of leptin in the activation of immune cells. Mediators Inflamm. 2010;2010:568343. 81. de Heredia FP, Gomez-Martinez S, Marcos A. Obesity, inflammation and the immune system. Proc Nutr Soc. 2012;71:332–8. 82. Horiguchi A, Ito K, Sumitomo M, Kimura F, Asano T, Hayakawa M. Decreased serum adiponectin levels in patients with metastatic renal cell carcinoma. Jpn J Clin Oncol. 2008;38:106–11. 83. Stryjecki C, Mutch DM. Fatty acid-gene interactions, adipokines and obesity. Eur J Clin Nutr. 2011;65:285–97. 84. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physiol Rev. 2013;93:1–21. 85. Norian LA, Rodriguez PC, O’Mara LA, Zabaleta J, Ochoa AC, Cella M, Allen PM. Tumor-infiltrating regulatory dendritic cells inhibit CD8? T cell function via L-arginine metabolism. Cancer Res. 2009;69:3086–94. 86. Norian LA, Kresowik TP, Rosevear HM, James BR, Rosean TR, Lightfoot AJ, Kucaba TA, Schwarz C, Weydert CJ, Henry MD, et al. Eradication of metastatic renal cell carcinoma after adenovirus-encoded TNF-related apoptosis-inducing ligand (TRAIL)/ CpG immunotherapy. PLoS One. 2012;7:e31085.
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IMMUNOLOGY AT THE UNIVERSITY OF IOWA
Effects of obesity on immune responses to renal tumors Vincent Chehval • Lyse A. Norian
Lyse A. Norian
Ó Springer Science+Business Media New York 2014
Abstract Kidney cancer incidence in the USA has been steadily increasing over the past several decades. The reasons for this are not completely clear, but an increased prevalence of known predisposing factors may be promoting this trend. Several major risk factors for kidney cancer have been identified. Among these, obesity is notable because its incidence has risen dramatically during this same period of time. Here, we will review the relationship between obesity and kidney cancer, and will explore the idea that obesity-mediated alterations in immune function may render immunotherapies for renal tumors ineffective. To support this idea, we will summarize characteristics of endogenous immune responses to renal tumors, as well as existing and developing immune-based therapies for kidney cancer patients. In doing so, we will highlight the ways in which altered immune function in obese individuals may render these therapies ineffective. Keywords
Obesity Kidney cancer Tumor immunity Immunotherapy
Kidney cancer: incidence and diagnosis Kidney cancer is one of the ten most common cancers in men and women in the USA. It can be broadly classified into three main types, depending on the location of the tumor and the age of the patient. Renal cell carcinoma (RCC) arises from the kidney parenchyma, which contains V. Chehval L. A. Norian (&) Department of Urology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA e-mail: [email protected] L. A. Norian Interdisciplinary Graduate Program in Immunology, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA L. A. Norian Holden Comprehensive Cancer Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA L. A. Norian Fraternal Order of Eagles Diabetes Research Center, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
the nephrons or filtering units of the kidney. Renal transitional cell carcinoma (RTCC) arises from the renal pelvis and calyces, which act as the collecting system of the kidney. Both RCC and RTCC occur in adults, whereas Wilms tumors occur in children. This review will focus on RCC, as it is the most common type of kidney cancer, and by itself accounts for nearly 2–3 % of all malignant tumors in US adults [1, 2]. RCC is one of the most lethal urologic tumors, with approximately 30–40 % of patients ultimately dying from their cancer. In the USA, about 65,000 new cases are diagnosed and about 13,500 patients die annually from RCC. Men develop RCC more frequently than women, and the overall male-to-female ratio is roughly 2:1. RCC is rare in children and young adults; the highest rates of diagnosis occur when individuals are in their 60s and 70s [1]. There are several different histologic types of RCC, with the most common being clear cell RCC (70– 80 %), papillary RCC (10–15 %), and chromophobe RCC (3–5 %) [3]. Several other rare variants have also been described. Renal tumors often remain asymptomatic until they are quite large or until advanced disease develops, and because of this, diagnosis is frequently delayed. Contrasted
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computed tomography (CT) scans of the abdomen and renal ultrasounds are the most commonly used imaging modalities for the diagnosis of RCC. However, magnetic resonance imaging (MRI) scans and kidney X-rays with dye, referred to as intravenous pyelograms (IVP), may also be used. It is estimated that over half of all renal tumors are diagnosed incidentally on imaging studies that were ordered for other reasons [3]. Fortunately, many tumors diagnosed in this manner are confined to the kidney and are associated with improved survival. For such localized tumors, the 5-year survival rate is 45–85 %, depending on the tumor stage and location [4]. Symptoms associated with local renal tumor growth include: blood in the urine (microscopic and visible), flank pain, development of bleeding around the kidney, and a palpable flank mass. Once tumors metastasize, the prognosis becomes much worse, with 5-year survival rates of 0–10 % [5]. Symptoms associated with metastatic disease may include: persistent cough, bone pain, pathologic bone fractures, weight loss, malaise, and cervical lymph node enlargement. The treatment of choice for organ-confined RCC remains surgical excision via radical or partial nephrectomy. However, even when primary surgery is successful, nearly 20–30 % of patients with localized RCC will experience tumor recurrence, and this typically happens within 3 years of surgery [1, 3, 5]. Metastatic disease is notoriously refractory to radiation therapy and chemotherapy. Therefore, immunebased therapies are among the most promising options for these patients, along with other biologic approaches that include targeted molecular therapies and anti-angiogenesis therapies [3]. The incidence of RCC has been slowly increasing since 1970, and numerous studies have examined possible reasons for this trend [2, 6]. Although increased diagnosis due to improved imaging techniques is likely part of the explanation, there are indications that the rate of de novo RCC formation is also increasing. In a study published in 2008, Decastro et al. [7] examined the confounding factors of increased use of abdominal imaging studies, increased age of the population, and other factors as potential reasons for the higher diagnosis rates of RCC. The authors found that the incidence of RCC was increasing independently of these factors. Thus, RCC tumors were arising more frequently, suggesting that the prevalence of one or more known predisposing factors was also increasing.
Obesity as a major risk factor for RCC Several risk factors for the development of RCC have been identified, with tobacco use, hypertension, and obesity at the top of the list [2, 8]. Prolonged tobacco smoke exposure and tobacco use of any kind is one of the most widely
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accepted risk factors for RCC, with a relative risk of 1.4– 2.5 compared with controls, meaning that for every one non-smoker who developed RCC, 1.4–2.5 smokers developed RCC [2]. All forms of tobacco use are implicated as RCC risk factors in a dose-dependent manner. However, as tobacco use has been steadily declining over the past several decades, it seems unlikely that tobacco could be causing the observed increases in RCC incidence. Hypertension has also been implicated as an independent risk factor for RCC in women [2, 9] and has been linked to increased mortality from RCC in men [9]. It is estimated that as of 2013, one in three US adults has high blood pressure [10]. Thus, it is possible that the widespread prevalence of hypertension could be contributing to the increased rates of RCC. More recently, obesity has become accepted as a major risk factor for RCC. According to CDC data for 2013, nearly 36 % of US adults are obese and another 33 % are overweight [11–13]. Using this information and the increasing rate of obesity since the 1970s, Finkelstein et al. [14] estimated that by 2030, 51 % of the American population will be obese. Obesity is most commonly defined as a body mass index (BMI) over 30, but other measures of obesity such as the percentage of visceral adipose tissue or the diameter of the peri-nephric fat pad are being used with increasing frequency [8, 15–17]. Multiple studies have indicated that the increased incidence of RCC in Western countries can be partially attributed to local increases in obesity, with some reports suggesting that 40 % or more of RCC cases in the USA are causally linked to obesity [2, 18, 19]. As obesity is also a risk factor for developing hypertension [20], it is possible that obesity may promote the formation of renal tumors in multiple ways: via direct effects on tumorigenesis and tumor progression and via indirect effects on cardiovascular function. A number of other factors have been implicated in the development of RCC, including lead exposure, diet, and numerous chemical compounds, but no direct causal relationship has been established for these factors [2]. The positive association between obesity and kidney cancer is one of the strongest in the field of oncology, and numerous studies have provided evidence of this trend. A 2001 review article by Bergstrom et al. [21] identified 24 studies that had examined the relationship between obesity and RCC development in Western countries between 1966 and 1998. Their evaluation showed that 21 out of 24 studies found an increased incidence of RCC in both men and women with elevated BMIs compared to those with lower BMIs. The authors determined that each unit of increased BMI was associated with a relative risk of RCC development of 1.07 (95 % CI 1.05–1.09). Translated into practical terms, this means that for approximately every 3 kg of increased body weight, the risk of RCC is increased by about 7 %. Similarly, a 2006 study involving 362,552
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Swedish men, followed from 1971 until death or the end of 1999, found a positive association between obesity and several cancer types, including RCC. Specifically, a relative risk of 1.8 was found for RCC in obese patients (95 % CI 1.4–2.4). This study also noted that as BMI increased linearly, the relative risk of RCC increased [22]. Results from the UK million-woman study published in 2007 revealed a significant link between obesity and the development of RCC. This study evaluated 1,222,630 women aged 50–64 from 1996 to 2001 and found that a 10-unit increase in BMI was associated with relative risk of developing RCC =1.53 (95 % CI 1.27–1.84) [23]. Comparable trends were identified in a 2012 study by BeebeDimmer et al. [19] in which 1,214 RCC subjects and 1,234 control subjects were analyzed; results from this study showed that obesity in early adulthood or within a 5-year period of time prior to diagnosis significantly increased the risk of developing RCC for white adults. More recently, a 2014 assessment of 156,774 participants in the US Women’s Health Initiative confirmed that increasing BMI is a predictor for RCC development [9], and a 2014 metaanalysis of 21 prior reports found an overall relative risk for developing RCC of 1.77 in obese versus lean men and women [18]. The effect of obesity on RCC progression is much less clear. Several reports have examined whether obesity is associated with more aggressive renal tumors, and their conclusions have been contradictory. In one retrospective study of 186 patients with localized renal tumors of\7 cm, an increased percentage of visceral adipose tissue was found to be an independent predictor of high-grade cancer [24], and another study illustrated that overweight patients with RCC are younger at diagnosis than are lean RCC patients [25], suggesting earlier tumorigenesis and/or heightened aggressiveness of tumor outgrowth. However, a 2012 report from the Mayo Clinic Rochester found that obesity was associated with the presence of less aggressive renal tumors and increased overall 5-year survival rates after nephrectomy (81.7 % for obese, 76.9 % for overweight, and 62.3 % for lean adults) [26]. Similar findings were reached in a Japanese study of 117 RCC patients undergoing nephrectomy; patients with increased visceral adipose tissue had lower-grade tumors and increased overall survival compared to lean study subjects [15]. In contrast, other studies have found no change in cancerspecific survival between obese and normal-weight RCC study subjects after nephrectomy [27]. Thus, although many studies have solidified the relationship between obesity and RCC, the effect of obesity on tumor progression and cancer-specific survival remains unclear. Importantly, the causes of increased RCC risk in obese adults remain unclear. Here, we will explore the hypothesis that obesity-mediated immune dysfunctions contribute to
enhanced tumor progression and diminished responses to immune-based therapies, an idea that has not yet been tested clinically.
Endogenous immune responses to RCC RCC is an immunogenic tumor, meaning that the immune system recognizes RCC-derived tumor antigens as foreign, and several efforts are underway to use this knowledge to improve outcomes for patients. At this time, the effect of obesity on endogenous immune responses to RCC is not known, so we will focus on general information regarding immunity to RCC in human subject studies that likely comprise both lean and obese adults. To better understand endogenous immune responses to RCC, we and others have examined systemic and local leukocyte subpopulations in human subjects with RCC. We found that the peripheral blood (PB) of RCC subjects contained significantly higher percentages of CD8? T cells that expressed B and Tlymphocyte attenuator (BTLA), a known marker of T cell functional exhaustion. Furthermore, the frequencies of BTLA? CD8? T cells increased with advancing tumor stage (Wald et al. 2014 Urologic Oncology, in press). A 2007 study found that nearly 70 % of the tumor-infiltrating leukocytes in RCC study subjects were CD3? T cells and 43 % were CD8? T cells [28]. In contrast, the authors found relatively few regulatory T cells, NK cells, or B cells within tumor masses. A 2013 study on systemic T cell responses to RCC found that although elevated percentages of myeloid and plasmacytoid dendritic cells were present in the PB of RCC patients, increased percentages of regulatory T cells were also present [29]. This report also examined local immune responses within RCC tumor tissue and found that the frequency of regulatory T cells was even higher in tumors than in PB. One of the most comprehensive evaluations of tumor-infiltrating lymphocytes in RCC is a 2012 study by Wang et al. [30]. In this report, the authors examined matched PB and tumor samples from 8 primary and 8 metastatic renal tumors. Although the sample size was small, this evaluation showed that the PB contained much higher percentages of CD8? T cells expressing CD27 than did renal tumors (approximately 80 vs 42 %). As CD27 ligation promotes enhanced T cell activation, differentiation, and survival, this suggests that CD8? T cells within renal tumors are less able to mediate protective anti-tumor immunity [31, 32]. In addition, RCC tumor-infiltrating CD8? T cells had a predominantly effector memory phenotype (CD62L-CD45RO?), whereas most CD8? T cells in the PB had a naive (CD62L? CD45RO-) or central memory (CD62L?CD45RO?) phenotype. Finally, the authors provided evidence to suggest that clonal expansion
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of RCC tumor-antigen-specific T cells occurred locally within the tumor [30]. Other groups have identified tumorinduced T cell anergy as a contributor to RCC advancement [33]. Thus, although tumor-specific T cells are present systemically and locally within RCC tumors, even before administration of immunotherapy, they may not be able to optimally exert protective immunity. T cell-mediated clearance of renal tumors may be inhibited by extrinsic factors as well. A study published in 2013 evaluated 35 RCC tumor specimens and peripheral blood samples from patients that ultimately developed metastatic RCC. Ten of the patients had metastatic disease at the time of nephrectomy, fourteen patients developed metastatic disease within 5 years of nephrectomy, and eleven patients developed metastatic disease 5 years after nephrectomy. Evaluation of PB samples revealed that those patients with metastatic disease at presentation had a significantly higher neutrophil/lymphocyte ratio (NLR) compared to those that developed metastatic disease after diagnosis [34]. In this same study, the authors also evaluated renal tumor cells for mRNA encoding the pro-apoptotic protein Fas ligand (Fas-L) typically found on the surface of cytotoxic T lymphocytes. Fas-L typically stimulates the Fas receptor on tumor cells, thereby activating tumor cell apoptosis. The study by Sejima et al. demonstrated that 21 out of 35 renal cancers contained cells expressing Fas-L mRNA including 10/11 of those patients diagnosed with metastatic disease, 9/14 of those diagnosed with metastatic disease within 5 years, and only 2/10 of those diagnosed with metastatic disease more than 5 years after nephrectomy, suggesting that the tumor cells were able to induce cytotoxic T cell apoptosis. The implication is that lower NLR ratios and lower Fas-L expression by tumor cells suggest stronger host immunity and slowed cancer progression [34]. Neutrophil accumulations have also been identified in late-stage RCC tumors by Minarik et al. [29], and higher levels of tumor-infiltrating neutrophils in RCC specimens have been associated with faster tumor recurrence and decreased overall survival [35]. As neutrophils are phenotypically similar to myeloid-derived suppressor cells (MDSCs), an immature cell population known to accumulate in cancer patients that inhibits T cellmediated anti-tumor activity, it is possible that ‘‘neutrophils’’ in such studies were actually MDSCs, thereby explaining why patients with lower NLR ratios had improved outcomes. MDSCs are known to impair T cell responses to RCC. We and others have found increased percentages of MDSCs in the PB and tumor masses of patients with RCC (Wald et al. 2014 Urologic Oncology, in press) and [33, 36, 37]. MDSCs inhibit T cell proliferation and decrease cytokine production through a variety of mechanisms, including local depletion of L-arginine supplies [38–41].
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Depleted local arginine levels decrease T cell proliferation, inhibit cytokine production, and decrease expression of the T cell antigen receptor CD3f [42]. In their 2005 paper, Zea et al. examined peripheral blood mononuclear cells (PBMCs) from 123 patients with metastatic RCC and compared them to PBMCs of cancer-free controls. The authors found that CD11b?CD14-CD15? MDSCs from patients with metastatic RCC displayed high levels of arginase activity, and depletion of these cells led to significant increases in T cell CD3f expression and IFNc production. These results again suggest that RCC leads to an environment of immunosuppression that is partially mediated by MDSCs. Along these same lines, a study that reviewed pathology slides from 306 patients with clear cell RCC found that increased tumor infiltration of mononuclear cells was associated with a twofold increase in allcause death and twofold increase in death from RCC [43]. Therefore, even though RCC incites protective T cell responses, the anti-tumor functions of effector cells generated will likely be blocked by MDSCs and/or other immunosuppressive leukocyte populations.
Current and future immunotherapies for RCC Taking the above information into account, current therapy for metastatic renal cell carcinoma is focused on immunebased therapies, targeted molecular therapies, and antiangiogenesis therapies. When disease is confined to the kidney, surgical excision is the treatment of choice. There is also evidence that patients with a solitary metastatic lesion or a limited number of resectable metastatic lesions benefit from surgical excision of those lesions. This concept holds true whether the lesions were discovered at the same time as the primary tumor or whether the lesions were discovered during surveillance after nephrectomy [44, 45]. Despite this, once metastatic disease is discovered, the average survival time is \1 year [46]. Even with this poor statistic, a survival advantage is seen in select patients with unrespectable metastatic disease who undergo removal of the primary renal tumor prior to receiving systemic therapy [47]. There are even isolated reports of spontaneous regression of metastatic lesions after removal of the primary tumor, but this is rare. Immunotherapies were some of the first systemic therapies to be developed for metastatic RCC. Interleukin-2 (IL-2) and IFN-a are the two most studied therapies. IL-2 therapy is postulated to mediate its anti-tumorigenic effects via activation of NK cells and effector T cells, but the exact mechanism of functioning in RCC remains unknown [46]. IFN-a is normally produced by lymphocytes and macrophages and initiates many downstream effects including enhanced antigen presentation and immunomodulation
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[46]. In a meta-analysis published in 2007, Hotte et al. [48] found that treatment regimens containing IL-2 were superior to regimens that did not contain IL-2. However, the results were modest, showing that IL-2 provided an increased response rate (measured via radiologic evidence of decreased tumor size) but no statistically significant survival advantage at 1 year. That being said, studies by the Rosenberg group at NCI have shown a 20 % objective response rate to high-dose IL-2 in patients with metastatic RCC; 9 % of treated patients showed complete and durable remission [49]. High-dose IL-2 has shown slightly improved response and cure rates when compared to standard dose IL-2 but is associated with substantial adverse side effects [50]. High-dose IL-2 is currently the only treatment that has shown the ability to cure metastatic RCC; however, the toxicity profile requires that it be reserved for patients with fewer medical problems and good performance status [50]. Many developing treatments for metastatic RCC are focused on immune-stimulatory therapies. Several vaccines are currently being tested, including IMA901. This vaccine was developed by comparing the mRNA expression profiles of RCC tumors to that of normal renal tissue. This process identified nine HLA-1 tumor- and one HLA-2 tumor-associated peptides (TUMAPs) that were highly overexpressed in cancerous tissue. The TUMAPs were then included in a vaccine which, when administered with a single dose of cyclophosphamide, was associated with longer overall survival, as compared to controls, in a recent Phase II trial [51]. Other vaccine trials currently underway involve AGS-003, which is a vaccine based on dendritic cells that is co-administered with the tyrosine kinase inhibitor, sunitinib. Preliminary results have shown improved overall progression-free survival with a low side effect profile. As sunitinib has been shown to decrease MDSC populations in RCC patients [52], it is possible that its inclusion here may be benefiting patients in multiple ways. Further trials of this approach are underway [53]. The promising results obtained in these vaccination studies reinforce the idea that boosting protective immunity can provide durable responses against advanced RCC. Other developing immune therapies for RCC focus on modulation of T cell functional status. Programmed Death 1 (PD1) is a cell surface receptor expressed by exhausted T cells. When T cells expressing this receptor come into contact with cells expressing the ligands (PD-L1 or PD-L2) for this receptor, the T cell response is downregulated [54]. It has been shown that patients with PD1-positive T cells tend to have larger tumors with an increased risk of metastasis and increased risk of cancer-specific death [54, 55]. As of 2014, several clinical trials using anti-PD-1 antibodies or anti-PDL1 antibodies are underway [54, 56– 58]. The rationale for these approaches is that blockade of
PD-1/PD-1 ligand interactions should prevent negative signals that initiate T cell exhaustion, thereby amplifying endogenous T cell responses to RCC. A preliminary study of 33 patients with advanced RCC published in 2012 showed a 27 % response rate to the therapy with a moderate side effect profile that would likely not preclude its use [56]. Other T cell therapies include antibodies to CTLA-4, an inhibitory T cell receptor associated with immunotolerance. Binding of CTLA-4 to its ligands B7.1 and B7.2 blunts ongoing T cell effector responses [59]. Ipilimumab is an anti-CTLA-4 antibody that is FDAapproved for use in melanoma and is being examined for use in RCC patients. One drawback to ipilimumab use is that it can produce serious side effects, including significant autoimmune events, in a minority of patients [60]. New studies combining ipilimumab with antibodies against PD-1 and/or PDL1 are underway, but effects of such combinatorial therapies in RCC are not yet known.
Obesity diminishes protective immune responses: effects on immunity to RCC? Given the fact that immunotherapies are being actively used and developed for the treatment of RCC, it is critical to understand how obesity might alter the efficacy of these therapies. There are numerous health concerns associated with obesity, including extensive detriments to the immune system. Obesity has been associated with a state of chronic inflammation characterized by elevated serum concentrations of the pro-inflammatory proteins C-reactive protein (CRP), IL-6, and TNF-a [61–63]. As chronic inflammation is known to inhibit protective immunity mediated by CD4? and CD8? T cells [39, 64, 65], it is not surprising that in humans, obesity is associated with decreased T and B cell proliferation, alterations in overall leukocyte counts, diminished production of antibodies after vaccinations, higher infection rates, and poor wound healing (reviewed in [66, 67] ). Specifically, reports have indicated that obesity is associated with increased total numbers of circulating CD3? T cells, primarily due to increased numbers of the CD4? subset accompanied by decreased numbers of CD8? T cells [68]. In this study, the subset composition of CD4? T cells was not examined, so it is not known whether the increased cells were effectors or regulatory T cells. Despite increases in total numbers, several studies have demonstrated that T cell function is compromised, as evidenced by decreased responses to mitogen stimulation [68– 70]. All of these factors suggest notable alterations to the immune system overall, and T cell immunity in particular, in obese individuals. Decreased T cell responsiveness would likely impair the efficacy of many immunotherapies currently being used or developed for RCC, such as high-
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Fig. 1 Mechanisms of obesity-mediated dysfunction in anti-tumor immunity: Obesity impacts protective immune responses in multiple ways. (1) Obesity is characterized by a state of chronic, systemic inflammation that is thought to originate from altered adipokine and cytokine secretion in white adipose tissue. Increased leptin and IL-6, and decreased adiponectin promote a systemic, pro-inflammatory host environment. (2) Obesity in mice has been linked to decreased dendritic cell (depicted in blue) entry into lymph nodes and a reduced ability of dendritic cells to stimulate the expansion of naive T cells. (3) T cells (depicted in gray) from obese mice and humans have diminished proliferative capacities, resulting in fewer effector T cells being generated. (4) Effector T cells that are produced may be more prone to exhaustion; high levels of PD-1 and BTLA have been found on CD8? T cells from RCC patients, but it is not clear whether these levels are further altered by obesity. (5) RCC tumors contain inhibitory MDSCs (depicted in red), and preliminary data suggest that local MDSCs’ prevalence is increased with obesity. Cumulatively, these factors would result in a more immunosuppressive, protumorigenic environment that would be refractory to immune-based therapies, an idea that has yet to be examined clinically
dose IL-2, vaccination therapies, anti-CTLA4, and antiPD1 or PD-L1 that rely upon T cell stimulation to mediate tumor clearance. Presently, direct support of this idea is not available from human studies. To date, much of the research examining the effects of obesity on immune function has been performed in mice and rats with genetic- or diet-induced obesity, and alterations in multiple cell types have been described. For example, several studies have shown that diet-induced obesity results in decreased frequencies of NK cells with reduced effector function [71, 72]. As NK cells can contribute substantially to tumor clearance even when present at low numbers, a loss in this cell population would promote accelerated tumor outgrowth. Other leukocyte populations are also impacted by obesity. We found that dietinduced obese mice had increased percentages of conventional DC in the spleen, but that these DC had a significantly decreased ability to induce CD8? T cell proliferation (Fig. 1) [73]. Our findings are in agreement with prior studies that had used bulk antigen-presenting cells from obese mice and found them to have a reduced
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ability to stimulate naive T cells [74, 75]. Phenotypically, we found no detectable alterations in splenic DC from lean and obese mice, so the cause of decreased stimulatory capacity in DC from obese mice remains unclear. Weitman et al. [76] recently reported that diet-induced obese mice have diminished fluid transport in lymphatic vessels, fewer lymphatic vessels, and decreased migration of DC and T cells into lymph nodes. These findings, when combined with our observations on the loss of DC function in obese mice, provide a compelling explanation for the reduced T cell responses [77] observed in obese rodents. In addition, others have shown that T cells from obese mice and rats have decreased proliferative responses to mitogen stimulation (Fig. 1) [78, 79], suggesting that T cell proliferative defects may be due to both extrinsic and intrinsic factors. In the context of anti-tumor immunity in response to immunotherapies, such changes in DC and T cell function would again be predicted to result in fewer endogenous, tumor-antigen-specific T cells becoming activated. Therefore, therapies such as tumor-antigen vaccines, antiCTLA4, and anti-PD-1, all of which rely upon effector T cell function, would likely show diminished efficacy in the clinic. An alternate source of immune modulation in obese individuals may stem from adipose tissue, rather than traditional primary or secondary immune organs. Leptin is a bioactive molecule secreted by adipocytes. It is structurally similar to IL-6 and can modulate activation of NK cells, production of pro-inflammatory cytokines, and stimulation of monocyte proliferation [80]. In animal models, the absence of leptin or leptin receptors has been associated with severe immune dysfunction, in addition to robust obesity. It has been shown that in obese individuals, circulating leptin levels increase, which in turn leads to a blunted central response to this molecule. Consequently, elevated circulating levels of leptin and activation of proinflammatory cells ensue [80, 81]. Adiponectin is another adipokine produced by fat cells, and its main function is as an anti-inflammatory molecule. Interestingly, in obese individuals, adiponectin levels are decreased, which further promotes systemic inflammation [11, 81]. The exact role these two molecules play in tumorigenesis is not yet fully understood; however, adiponectin levels have been shown to be reduced in patients with metastatic RCC and to correlate inversely with tumor size [82]. Other proposed mechanisms for the pro-inflammatory environment seen in obese individuals include increased fatty acid production, which directly stimulates TNF-a and IL-6 production from adipocytes, and adipose tissue growth outstretching its vascular supply leading to hypoxia, cell death, and inflammation [83, 84]. The interplay of all these factors is complex, and their net effects on immune function are not fully understood. However, it is clear that obesity is a pro-
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inflammatory condition with numerous adverse effects on cell-mediated immunity. How then does obesity impact immune responses to RCC, in the presence or absence of immune-based therapies? We have begun to examine this question using normal-weight mice and diet-induced obese mice with orthotopic RCC. We surgically implanted the syngenic renal tumor line Renca into age-matched lean and obese BALB/c mice [73]. We found that obese mice had profound alterations in their serum cytokine/chemokine profile, as marked by upregulation of 15 different proteins, including IL-1a, IL-7, IL-13, IL-17, and IP-10. Following tumor challenge, obese mice had a transient increase in renal tumor burden at day 7 post-tumor challenge, but this difference was not present at later time points. Upon examining tumor-bearing kidneys from obese mice, we found increased percentages of CD11b? DC. Instead of stimulating CD8? T cell expansion, these renal DC acted as regulatory cells [85] to inhibit T cell proliferation. To evaluate the effects of obesity on RCC treatment, we administered a DC- and T cell-dependent immunotherapy [86] at day 7 after tumor challenge. This therapy induced tumor regression in lean mice, and 80 % of treated lean mice cleared their tumors and survived through day 70. In contrast, the same therapy was not effective in obese mice; progressive tumor outgrowth was observed, and 100 % of obese mice succumbed to their renal tumors. Evaluation of renal tumors in the obese mice again revealed an increased percentage of regulatory DCs and decreased percentages of IFNc-producing CD8? T cells [73]. In addition, we have found that renal tumors and spleens from obese mice have increased percentages of MDSCs, with significant increases present by day 14 after tumor challenge; although the suppressive capacity of these cells is unchanged on a percell basis, the greater number of MDSCs in renal tumors and spleens would act to block protective T cell immunity (unpublished results). Our results, when combined with findings from other groups using obese tumor-free mice, suggest that obesity not only causes immune dysfunction, but also impairs protective responses to immune-based therapies for RCC (Fig. 1). It remains to be seen whether obese RCC patients have a similar loss of immunotherapeutic efficacy.
Summary RCC is a prevalent disease with an unfortunate propensity to metastasize. Obesity is a major predisposing factor for developing RCC, but the causes for this association remain unclear. RCC is one of the most immunogenic tumors known, and endogenous anti-tumor immune responses can be enhanced through the use of targeted immunotherapies.
Although immune-based therapies for advanced RCC have shown promise in a subset of patients, significantly more work is needed to achieve objective responses in a majority of treated individuals. For this reason, new immune-based treatments for RCC are actively being explored. However, given the facts that obesity is concurrently rising at an alarming rate and that obesity is known to impair normal immune function, it is possible that any new immunotherapy for metastatic RCC will have reduced efficacy in obese patients. Moving forward, immune-based therapies (vaccines and T cell modulators) appear to be at the forefront of treatment options for advanced RCC. It is unknown whether their effectiveness will be durable in the coming years as obesity continues to increase. Acknowledgments This work was supported by a National Cancer Institute Grant (# 1 R01 CA181088-01) to LAN.
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