MOLECULAR & CELLULAR ONCOLOGY 2016, VOL. 3, NO. 4, e1163005 (2 pages) http://dx.doi.org/10.1080/23723556.2016.1163005
AUTHOR’S VIEW
Exercise: A new role for an old tool Manja Idorna and Per thor Stratena,b a Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Denmark; bDepartment of Immunology and Microbiology, University of Copenhagen, Denmark
ABSTRACT
ARTICLE HISTORY
We recently demonstrated that voluntary exercise leads to an influx of immune cells in tumors and a greater than 60% reduction in tumor incidence and growth across several mouse models. Improved immunological control of tumor progression may have important clinical implications in the prevention and treatment of cancer in humans.
Received 3 February 2016 Accepted 6 April 2016
Exercise has been shown to improve functional capacity and patient-reported outcomes across a range of cancer diagnoses.1 The mechanisms behind this protection are largely unknown, but exercise-mediated changes in body composition, sex hormone levels, systemic inflammation, and immune cell function have been suggested to play a role.2 We recently demonstrated that voluntary exercise (wheel running) led to a greater than 60% reduction in tumor incidence and growth across several murine tumor models, including transplanted tumor (B16 melanoma and Lewis lung cancer), chemically induced (diethylnitrosamine [DEN]) liver cancer, and a spontaneous melanoma model.3 Using the B16 melanoma model we scrutinized in detail the mechanism by which exercise inhibited tumor growth and found by microarray assay that pathways associated with immune function were significantly upregulated in tumors from exercise animals. These data were substantiated at the cellular level using immunohistochemistry (IHC) and flow cytometry, which showed that tumors from exercise animals were characterized by a denser infiltration of immune cells consisting of T cells, B cells, dendritic cells, and NK cells. In particular, the number of NK cells was increased in tumors from exercise animals and depletion of NK cells blunted the exercise-dependent suppression of tumor growth, demonstrating that NK cells were necessary and sufficient for the effect, at least in the fast growing transplantable B16 melanoma model.3 Importantly, we demonstrated that NK cells were engaged through an epinephrine-dependent mobilization, and blockade of this response by b-adrenergic blockade (propranolol) blunted the exercise-dependent tumor inhibition.3 The data summarized above could have several important implications in humans, both in relation to cancer incidence and therapy. First, the mechanism of mobilization of NK cells in the mouse model that is mediated by epinephrine via b-adrenergic receptors on NK cells is also relevant in humans; an increase in systemic NK cell frequencies is a key immunological feature of exercise in humans.4 Also, NK cells in humans and mice are quite similar functionally and are capable of recognizing and
CONTACT Per thor Straten © 2016 Taylor & Francis Group, LLC
[email protected]
KEYWORDS
Exercise; immune infiltration; NK cells; tumor growth
killing cancer cells. Accordingly, these data are likely to be relevant not just for mice, but also for humans. Obviously, it will take huge studies of various behavioral aspects over a substantial time span to fully study the protective role of exercise in human cancer. However, a key feature of the protective role of exercise in our mouse studies was an increased number of immune cells in tumors from exercise animals3 and this feature can be studied in humans by serial biopsies before and after exercise. Thorough studies of the composition of immune cells infiltrating the tumor might reveal data supporting the notion of improved immunological control of tumor progression, and could set the stage for combination treatment as described in more detail below. Second, although NK cells were responsible for the protective effect, at least in the fast growing transplantable B16 melanoma model, we have no evidence that this is the case using more clinically relevant tumor models. Our data showed that the most pronounced effect was achieved when the mice exercised prior to inoculation of cancer cells, suggesting that killing of cancer cells at the inoculation site or very early in tumor establishment plays a key role in the immunological control of tumor progression by NK cells. Thus, in terms of translation to a human setting, maybe the most important finding is the impact on exercise using the chemically induced model (DEN) or the spontaneous melanoma model. In the DEN model, tumor incidence was decreased from 70% to 30% by exercise and the tumors that did develop were smaller. Given that fact that the immune infiltrate in the B16 model showed a significant increase not only in NK cells, but also in dendritic cells, B cells, and T cells, it could be speculated that in these slow growing clinically relevant models NK cells may provide the “spark” but other immune subsets play a more important role in slowing tumor progression. This notion is supported by the fact that solid tumors contain very few NK cells, whereas T cells may be present in more substantial numbers. 5 Third, given the recent breakthroughs of immunotherapy in cancer, exercise could potentially play a role in conditioning the
e1163005-2
M. IDORN AND P. THOR STRATEN
response to treatment. To this end, recently approved immunotherapies of cancers such as melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC)—the “check point inhibitor” antibodies—induce clinical responses by unleashing tumor-specific immune responses at the tumor site.6 Importantly, several lines of data suggest that patients harboring tumors with a brisk infiltration of immune cells are more likely to respond to treatment.7 Thus, exercise could represent a tool to condition patients to respond to immunotherapy by increasing the immune infiltrate in the tumor. Another breakthrough in immunotherapy of cancer is adoptive cell transfer (ACT) using tumor infiltrating lymphocytes (TILs) that are expanded in vitro and administered back to the patient. In particular, approximately 50% of melanoma patients respond to such treatment, with a stunning 20% experiencing lasting complete responses.8,9 Obviously, a prerequisite for TIL-based ACT is immune infiltrates, and it is possible that exercise could promote the quantity, and maybe the quality, of the infiltrating cells. Moreover, the immune system has been suggested to also be crucial for the efficacy of chemotherapy. If these findings are substantiated by human studies, exercise could play a role in improving the response to conventional treatments.10
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References 1. Pedersen L, Christensen JF, Hojman P. Effects of exercise on tumor physiology and metabolism. Cancer J 2015; 21:111-6; PMID:25815851; http://dx.doi.org/10.1097/PPO.0000000000000096
2. McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer 2008; 8:205-11; PMID:18235448; http://dx.doi.org/10.1038/ nrc2325 3. Pedersen L, Idorn M, Olofsson GH et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism 2016 Mar 8; 23 (3):554-62; http://dx.doi.org/10.1016/j.cmet.2016.01.011. 4. Bigley AB, Rezvani K, Chew C et al. Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Brain Behav. Immun. 2014; 39:160-71. doi: 10.1016/j.bbi.2013.10.030. Epub;%2013 Nov 5.:160–171; PMID:24200514; http://dx.doi.org/ 10.1016/j.bbi.2013.10.030 5. Stojanovic A, Correia MP, Cerwenka A. Shaping of NK cell responses by the tumor microenvironment. Cancer Microenviron 2013; 6:13546; PMID:23242671; http://dx.doi.org/10.1007/s12307-012-0125-8 6. Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr. Opin.Immunol 2015; 33C:2335; PMID:25621841; http://dx.doi.org/10.1016/j.coi.2015.01.006 7. Spranger S, Koblish HK, Horton B et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer 2014; 2:1-14; PMID:24829758; http://dx.doi.org/10.1186/ 2051-1426-2-3 8. Andersen R, Donia M, Ellebaek E et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL-2 regimen. Clin. Cancer Res. epub ahead of print. PMID:27006492 9. Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17:4550-7; PMID:21498393; http://dx.doi.org/10.1158/1078-0432.CCR-11-0116 10. Sistigu A, Yamazaki T, Vacchelli E et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 2014; 20:1301-9; PMID:25344738; http://dx.doi.org/10.1038/nm.3708
AUTHOR’S VIEW
Exercise: A new role for an old tool Manja Idorna and Per thor Stratena,b a Center for Cancer Immune Therapy (CCIT), Department of Hematology, University Hospital Herlev, Denmark; bDepartment of Immunology and Microbiology, University of Copenhagen, Denmark
ABSTRACT
ARTICLE HISTORY
We recently demonstrated that voluntary exercise leads to an influx of immune cells in tumors and a greater than 60% reduction in tumor incidence and growth across several mouse models. Improved immunological control of tumor progression may have important clinical implications in the prevention and treatment of cancer in humans.
Received 3 February 2016 Accepted 6 April 2016
Exercise has been shown to improve functional capacity and patient-reported outcomes across a range of cancer diagnoses.1 The mechanisms behind this protection are largely unknown, but exercise-mediated changes in body composition, sex hormone levels, systemic inflammation, and immune cell function have been suggested to play a role.2 We recently demonstrated that voluntary exercise (wheel running) led to a greater than 60% reduction in tumor incidence and growth across several murine tumor models, including transplanted tumor (B16 melanoma and Lewis lung cancer), chemically induced (diethylnitrosamine [DEN]) liver cancer, and a spontaneous melanoma model.3 Using the B16 melanoma model we scrutinized in detail the mechanism by which exercise inhibited tumor growth and found by microarray assay that pathways associated with immune function were significantly upregulated in tumors from exercise animals. These data were substantiated at the cellular level using immunohistochemistry (IHC) and flow cytometry, which showed that tumors from exercise animals were characterized by a denser infiltration of immune cells consisting of T cells, B cells, dendritic cells, and NK cells. In particular, the number of NK cells was increased in tumors from exercise animals and depletion of NK cells blunted the exercise-dependent suppression of tumor growth, demonstrating that NK cells were necessary and sufficient for the effect, at least in the fast growing transplantable B16 melanoma model.3 Importantly, we demonstrated that NK cells were engaged through an epinephrine-dependent mobilization, and blockade of this response by b-adrenergic blockade (propranolol) blunted the exercise-dependent tumor inhibition.3 The data summarized above could have several important implications in humans, both in relation to cancer incidence and therapy. First, the mechanism of mobilization of NK cells in the mouse model that is mediated by epinephrine via b-adrenergic receptors on NK cells is also relevant in humans; an increase in systemic NK cell frequencies is a key immunological feature of exercise in humans.4 Also, NK cells in humans and mice are quite similar functionally and are capable of recognizing and
CONTACT Per thor Straten © 2016 Taylor & Francis Group, LLC
[email protected]
KEYWORDS
Exercise; immune infiltration; NK cells; tumor growth
killing cancer cells. Accordingly, these data are likely to be relevant not just for mice, but also for humans. Obviously, it will take huge studies of various behavioral aspects over a substantial time span to fully study the protective role of exercise in human cancer. However, a key feature of the protective role of exercise in our mouse studies was an increased number of immune cells in tumors from exercise animals3 and this feature can be studied in humans by serial biopsies before and after exercise. Thorough studies of the composition of immune cells infiltrating the tumor might reveal data supporting the notion of improved immunological control of tumor progression, and could set the stage for combination treatment as described in more detail below. Second, although NK cells were responsible for the protective effect, at least in the fast growing transplantable B16 melanoma model, we have no evidence that this is the case using more clinically relevant tumor models. Our data showed that the most pronounced effect was achieved when the mice exercised prior to inoculation of cancer cells, suggesting that killing of cancer cells at the inoculation site or very early in tumor establishment plays a key role in the immunological control of tumor progression by NK cells. Thus, in terms of translation to a human setting, maybe the most important finding is the impact on exercise using the chemically induced model (DEN) or the spontaneous melanoma model. In the DEN model, tumor incidence was decreased from 70% to 30% by exercise and the tumors that did develop were smaller. Given that fact that the immune infiltrate in the B16 model showed a significant increase not only in NK cells, but also in dendritic cells, B cells, and T cells, it could be speculated that in these slow growing clinically relevant models NK cells may provide the “spark” but other immune subsets play a more important role in slowing tumor progression. This notion is supported by the fact that solid tumors contain very few NK cells, whereas T cells may be present in more substantial numbers. 5 Third, given the recent breakthroughs of immunotherapy in cancer, exercise could potentially play a role in conditioning the
e1163005-2
M. IDORN AND P. THOR STRATEN
response to treatment. To this end, recently approved immunotherapies of cancers such as melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC)—the “check point inhibitor” antibodies—induce clinical responses by unleashing tumor-specific immune responses at the tumor site.6 Importantly, several lines of data suggest that patients harboring tumors with a brisk infiltration of immune cells are more likely to respond to treatment.7 Thus, exercise could represent a tool to condition patients to respond to immunotherapy by increasing the immune infiltrate in the tumor. Another breakthrough in immunotherapy of cancer is adoptive cell transfer (ACT) using tumor infiltrating lymphocytes (TILs) that are expanded in vitro and administered back to the patient. In particular, approximately 50% of melanoma patients respond to such treatment, with a stunning 20% experiencing lasting complete responses.8,9 Obviously, a prerequisite for TIL-based ACT is immune infiltrates, and it is possible that exercise could promote the quantity, and maybe the quality, of the infiltrating cells. Moreover, the immune system has been suggested to also be crucial for the efficacy of chemotherapy. If these findings are substantiated by human studies, exercise could play a role in improving the response to conventional treatments.10
Disclosure of potential conflicts of interest No potential conflicts of interest were disclosed.
References 1. Pedersen L, Christensen JF, Hojman P. Effects of exercise on tumor physiology and metabolism. Cancer J 2015; 21:111-6; PMID:25815851; http://dx.doi.org/10.1097/PPO.0000000000000096
2. McTiernan A. Mechanisms linking physical activity with cancer. Nat Rev Cancer 2008; 8:205-11; PMID:18235448; http://dx.doi.org/10.1038/ nrc2325 3. Pedersen L, Idorn M, Olofsson GH et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism 2016 Mar 8; 23 (3):554-62; http://dx.doi.org/10.1016/j.cmet.2016.01.011. 4. Bigley AB, Rezvani K, Chew C et al. Acute exercise preferentially redeploys NK-cells with a highly-differentiated phenotype and augments cytotoxicity against lymphoma and multiple myeloma target cells. Brain Behav. Immun. 2014; 39:160-71. doi: 10.1016/j.bbi.2013.10.030. Epub;%2013 Nov 5.:160–171; PMID:24200514; http://dx.doi.org/ 10.1016/j.bbi.2013.10.030 5. Stojanovic A, Correia MP, Cerwenka A. Shaping of NK cell responses by the tumor microenvironment. Cancer Microenviron 2013; 6:13546; PMID:23242671; http://dx.doi.org/10.1007/s12307-012-0125-8 6. Shin DS, Ribas A. The evolution of checkpoint blockade as a cancer therapy: what’s here, what’s next? Curr. Opin.Immunol 2015; 33C:2335; PMID:25621841; http://dx.doi.org/10.1016/j.coi.2015.01.006 7. Spranger S, Koblish HK, Horton B et al. Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells directly within the tumor microenvironment. J Immunother Cancer 2014; 2:1-14; PMID:24829758; http://dx.doi.org/10.1186/ 2051-1426-2-3 8. Andersen R, Donia M, Ellebaek E et al. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL-2 regimen. Clin. Cancer Res. epub ahead of print. PMID:27006492 9. Rosenberg SA, Yang JC, Sherry RM et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011; 17:4550-7; PMID:21498393; http://dx.doi.org/10.1158/1078-0432.CCR-11-0116 10. Sistigu A, Yamazaki T, Vacchelli E et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat Med 2014; 20:1301-9; PMID:25344738; http://dx.doi.org/10.1038/nm.3708
