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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy

Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of epigenetic modulators, such as histone deacetylase (HDAC) inhibitors, in cancer therapy. HDAC inhibitors have been approved as single agents for cutaneous and peripheral T-cell lymphoma and have shown promising activity in reversing therapy resistance in other tumor types. The effects of HDAC inhibitors on immune modulation have created a recent interest in their potential role in immunotherapy. This review describes the current understanding on integrating HDAC inhibitors into various immunotherapeutic approaches, such as cancer vaccines, adoptive T-cell transfer and immune checkpoint inhibitors. Furthermore, it summarizes promising treatment strategies in epigenetic immune priming from clinical trials that are currently underway.

Jeenah Park1, Scott Thomas1 & Pamela N Munster*,1 1 Department of Medicine, Hematology/ Oncology Division, University of California, San Francisco, CA 94115, USA *Author for correspondence: Tel.: +1 415 885 7810 Fax: +1 415 353 7779 pmunster@ medicine.ucsf.edu

Keywords:  adoptive T-cell transfer • cancer • epigenetics • HDAC inhibitors • immune checkpoint inhibitors • immunotherapy • immune response • vaccines

Progress made in cancer biology in the last two decades has led to a paradigm shift in cancer treatment. Initial therapeutic efforts predominantly based on cytotoxic therapy have been expanded to include specific targeted biologics based on mutational and mechanistic insights. More recently, the adaptive immune responses have been successfully exploited as a novel means to cancer therapy with long-lasting tumor control. Unlike the more global assault on tumors with cytotoxic therapy, the approach to antitumor therapy nowadays involves more specific interruption of select pathway activation, reversal of oncogenic events and i­nduction of sustained antitumor immune response. In addition to specific mutations that activate key oncogenes or reduce the function of tumor suppressors [1] , an increasing awareness of the role of epigenetic changes in tumorigenesis has brought more attention to the epigenetic modulators [2] . Epigenetic alterations affect gene expression by modifying chromatin structure without changing the sequence of DNA. Genes can be epigenetically regulated and, in the case

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of tumor suppressors, silenced by histone modifications, DNA methylation or nucleosomal remodeling [2] . Tumor-specific methylation changes and aberrant histone acetylation patterns have been frequently reported in cancer [3–6] . Since epigenetic changes are thought to be adaptive and heritable, they may further contribute to resistance to anticancer therapy. Histone deacetylase (HDAC) inhibitors have been investigated in cancer therapy for their ability to modulate gene expression. HDAC inhibition has been shown to suppress angiogenesis by downregulating pro-angiogenic factors and to selectively induce apoptosis in tumor cells by activating death pathways [7–9] . Extensive clinical studies have shown that the effects of HDAC inhibitors and DNA methyltransferase (DNMT) inhibitors are limited as single agents  [10] , but they have promising activity in reversing resistance to different cancer therapies, including hormone therapy, chemotherapy and radiotherapy. A large body of work has further suggested an important role of HDAC inhibitors as immune-regulators.

Epigenomics (2015) 7(4), 641–652

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Review  Park, Thomas & Munster Cancer immunotherapy relies on the host’s immune system to eliminate tumor cells by targeting cancer antigens, blocking immune checkpoints or counteracting adaptive immune suppression [11] . Restoring an immune response has successfully been exploited by several means: vaccines that harness cancer antigens, adoptive T-cell transfer that enriches tumor antigenspecific T cells and monoclonal antibodies (mAb) that block immune checkpoints. CTLA4, an inhibitory signal for T-cell activation, was the first immune checkpoint receptor to be targeted in clinical studies. The success of ipilimumab (Yervoy; Bristol-Myers Squibb, NY, USA), an anti-CTLA4 antibody, in Phase III clinical trials has revealed survival benefit for patients with metastatic melanoma [12] and validated the concept of adaptive immunotherapy and long-lasting antitumor response through immune modulation. Programmed cell death (PD-1) is another inhibitory receptor expressed by T cells. Targeting PD-1 has shown that the interaction between the receptor and its ligands (PD-L1 and PD-L2) that are found on tumors and stromal cells plays an important role in the adaptive immune response in many tumors. PD-1 and PD-L1 inhibitors have shown promising activity in several cancers, including non-small-cell lung cancer (NSCLC) and renal cell carcinoma [13,14] . Pembrolizumab (Keytruda; Merck, NJ, USA) and nivolumab (Opdivo; BristolMyers Squibb) are two inhibitory PD-1 antibodies that have recently been approved for treatment of advanced melanoma. Immune checkpoint inhibitors are now being explored in combination with cytotoxic therapy, activated pathway inhibitors and biologic therapy. It has been suggested that HDAC inhibitors [10] , as with DNA hypomethylating agents [15] , may be more effective when combined with other therapies. Tumor cell death induced by HDAC inhibitors is thought to provide antigens that can be detected by the immune system, thus sensitizing tumor cells to immune-mediated destruction and potentiating the efficacy of immunotherapies. This review will discuss the findings from preclinical and clinical studies that investigated synergistic activities of HDAC inhibitors and immunotherapeutic strategies. While initial reports are promising, the principles of epigenetic immune priming will require extensive studies to determine the ideal patient setting, timing and sequence of the th­erapies that will maximize treatment efficacy. Why target the epignome Epigenetic modifications allow adaptable and heritable changes in gene expression. Histone acetyltransferases (HATs) and HDACs are key enzymes in remodeling chromatin by acetylation and deacetylation of histone proteins and thereby regulating the expression of a

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large range of genes involved in physiological processes, including apoptosis [7] . Epigenetic changes drive cancer cells to altered signaling pathways, hence providing selective advantages for tumor progression [16] . Heritable adaptation through epigenetic modification has increasingly been recognized in the emergence of therapy resistance [17] . Consequently, strategies to reverse aberrant epigenetic states are being actively explored for cancer treatment. Biological effects of acetylation in cancer cells

Protein acetylation regulates a myriad of cellular systems that control tumor cell function and fate, including differentiation, migration and invasion, DNA damage response, metabolism, cell cycle progression and apoptosis. This degree of influence results from regulating accessibility of transcriptional machinery to target promoters through acetylation of histone tails as well as controlling protein/enzymatic function by direct acetylation [18] . Given a broad role of acetylation in cell biology, disturbing this mechanism manifests in the alteration of many key signaling pathways that influence tumorigenesis [19,20] . Beyond regulating the interaction of nucleosomes with DNA, acetylation exerts its effect on a growing number of nonhistone proteins by modulating protein–DNA and protein–protein interaction, protein stability and enzymatic activity [21] . Many transcription factors are recruited to target promoters together with co-activator and repressor complexes that include HATs and HDACs. In addition to influencing chromatin structure through histones, acetylation of transcription factors affects their affinity for DNA binding. For instance, acetylation of the transcription factor p53 increases its binding to DNA and the transactivation of its target genes [22] . The activity of p53 is essential to a cell’s response to stress or DNA damage and is often lost in tumors. On the other hand, acetylation of the forkhead family of tumor suppressing transcription factors reduces DNA binding potential, resulting in increased tumor cell proliferation [23,24] . Acetylation can also exert opposing effects on different proteinprotein interactions. Microtubules are an assemblage of α/β-tubulin dimers whose dynamicity is essential, especially for chromosome capture and segregation during cell division. Acetylation of α-tubulin helps to stabilize the microtubule, preventing its depolymerization [25] . In tumor cells, altering these dynamics during cell division can result in chromosome mis-segregation or mitotic catastrophe and cell death. In contrast, acetylation of the DNA damage response protein ku70 attenuates its interaction with the pro-apoptotic driver Bax, allowing freed Bax to compromise mitochondrial integrity and initiate apoptosis [26] .

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy 

Thus, post-translational acetylation can influence protein function via multiple mechanisms. To this point, transcription factors, as a group, appear to be a primary target of acetylation, which is not surprising given that they function in conjunction with HAT and HDAC containing complex at target promoters. However, this apparent bias towards modulation of transcription machinery by acetylation may disappear with an increased understanding of the acetylome. The HDAC family

HDACs remove the acetyl groups from lysine residues of proteins [27] . HDACs have been shown to deacetylate many nonhistone proteins as well [28,29] . Eighteen HDACs that have been identified in humans are classified into four classes based on structural homology to yeast HDACs, subcellular localization and enzymatic activity  [27] . The class I HDACs (HDAC1, HDAC2, HDAC3, HDAC8) are homologous to the yeast RPD3 protein and are expressed in the nucleus of all cells. The class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) and the class IIb HDACs (HDAC6, HDAC10) are homologous to the yeast Hda1 protein and are expressed in the nucleus as well as the cytoplasm. The class III HDACs (sirtuins 1–7) are homologous to the yeast protein Sir2. Only HDAC11 belongs to the class IV HDAC group. Furthermore, HDAC classes I, II and IV utilize Zn2+ for their enzymatic activity, while class III HDACs require the c­oordination of the cofactor NAD +. HDACs as targets for cancer therapy

Growing evidence demonstrates that HDACs are overexpressed in various cancers, such as colon cancer [30] , breast cancer [31] , prostate cancer [32] and acute myeloid leukemia  [33] . Dysregulation of chromatin modification by HDACs contributes to aberrant gene expression in human cancers. Some studies indicate a correlative relationship between altered expression of HDACs and increased tumor aggressiveness [31] and accelerated cell proliferation  [34] . However, caution should be taken in using the level of HDAC expression as a prognostic marker in survival as there is inconsistency between in vitro and in vivo data. In addition to altered expression of HDACs in cancer, select inhibition of individual HDACs can reverse or prevent cancer therapy resistance. For example, genetic or pharmacologic inhibition of HDAC2 has been shown to reverse hormone therapy resistance by aberrantly regulating the estrogen receptor and its activation of nonclassical signaling pathways [35] . Similarly, inhibition of HDAC1 and HDAC2 resensitizes chronic lymphocytic leukemic cells to cell death induced by tumor necrosis factor-related apoptosis-

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inducing ligand [36] . In prostate cancer, knockdown of HDAC1 and HDAC3 suppresses expression of androgen receptor-regulated genes, recapitulating the transcriptional effects of HDAC inhibitor treatment [37] . Such findings suggest a fundamental role of HDACs in tumorigenesis. Recently, it has become evident that tumors evade host immunity by creating an immunosuppressive microenvironment. There is strong evidence that regulatory T (Treg ) cells, reported in higher levels in cancer patients [38] , interfere with antitumor immune response. Therefore, an approach to reduce tumordriven immune suppression is to target Treg cells [39] . However, there are conflicting results regarding the effect of HDAC inhibitors on immune cells, such as CD8 + T cells and Foxp3+ Treg cells. One study noted that the addition of entinostat increased antigen-specific, highly functional antitumor T cells while selectively reducing Treg cells [40] . Similarly, another study showed that entinostat downregulated Foxp3 expression, resulting in Treg suppression [41] . On the contrary, opposite effects on Foxp3 upon HDAC inhibition have been reported by other investigators [42–44] . For instance, a group reported that treatment of mice with trichostatin A increased the numbers and suppressive function of Treg cells [42] . Further studies are needed to determine whether these effects are dependent on select HDAC inhibitor class, specific HDAC inhibitor or the dose of the agents. Moreover, the multilevel molecular regulation of Foxp3 by HDACs on its gene locus, post-translational modification and direct acetylation [45] should be carefully examined in different states of T-cell activation and placed in context with surrounding cellular effects of HDACs on lymphocytes and myeloid cells. Since regulation of Treg cells is critical for successful cancer immunotherapy, more work is needed to elucidate the immune-modulatory mechanism of HDAC inhibition. Pharmacological modulation of the epigenome The first generation of HDAC inhibitors includes compounds, such as romidepsin (Istodax; Celgene, NJ, USA), valproic acid and trichostatin A. The second generation of HDAC inhibitors fall in two categories: hydroxamic acids and benzamides [46] . Panobinostat and vorinostat (Zolinza; Merck) are hydroxamic acids that function as pan-HDAC inhibitors that can target all zinc-dependent HDACs (Figure 1) . Entinostat is an extensively investigated member of the benzamide class that selectively targets HDAC 1, 2 and 3 [47] . Vorinostat and romidepsin have been approved for the treatment of cutane-

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Class

Inhibitors I HDAC member

1

2

IIa 3

8

4

5

IIb 7

9

6

10

III

IV

Sir

11

Romidepsin (FK228) Entinostat (MS-275) Chidamide (HBI-8000) Valproic acid (VPA) Panobinostat (LBH589) Trichostatin A (TSA) Vorinostat (SAHA)

Figure 1. List of select histone deactylase inhibitors and their histone deactylase targets. Sir: Sirtuin.

ous T-cell lymphoma (CTCL) in 2006 and 2009, respectively  [48] . Other reviews have summarized a list of completed and active clinical trials that assessed the efficacy of HDAC inhibitors against various cancers [49–51] . Despite the possibility of HDAC inhibitors having a global effect on histone modification, studies have surprisingly found that cancer cells exhibit altered expression in fewer than 10% of genes following HDAC inhibition [52–54] . It is unclear why disruption of the chromatin remodeling process by HDAC inhibition does not cause global changes in gene expression. However, this limited effect on gene transcription may be the reason why these inhibitors have generally exhibited an acceptable safety profile in patients being evaluated against a variety of solid and hematologic malignancies [55] . Whereas vorinostat is effective in treating advanced CTCL, it has demonstrated limited anticancer activity against solid tumors as a single agent in Phase I and II trials [56–59] . Nonetheless, investigators have continued to assess vorinostat as a part of combination therapy in solid tumors due to its tolerable toxicities and promising activity. The recent designation of breakthrough status of entinostat in the reversal of hormonal therapy resistance has sparked further interest in the development of subsequent generations of HDAC inhibitors for combination with other therapies. Given their role in sensitization of cancer cells to immunerelated destruction, HDAC inhibitors have recently been tested in combination with immunotherapeutic approaches to achieve more potent, longer lasting cytotoxicity [60] . The next two sections of this review describe preclinical and clinical studies that have evaluated the efficacy of combining HDAC inhibitors with various immunotherapy treatments and validated their potential to prime tumor cells for immune-mediated cell death.

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Preclinical studies of HDAC inhibitors & immunotherapy combination HDAC inhibitors & cancer vaccines

Cancer vaccines stimulate the patient’s immune system to prevent tumorigenesis (prophylactic) or delay cancer progression (therapeutic). They activate a select group of B and T cells that recognize tumor-associated antigens and induce the release of cytotoxic molecules that kill tumor cells. Therapeutic cancer vaccines are developed using antigens from cancer cells (peptide or proteinbased), nucleic acids that contain genetic information for synthesizing tumor-associated antigens (DNA or RNAbased) or weakened cancer cells carrying a specific antigen [61] . Sipuleucel-T (Provenge; Dendreon, WA, USA) is the first dendritic cell-based cancer vaccine, which was approved for the treatment of metastatic prostate cancer  [62,63] . In addition, an emerging body of literature suggests that oncolytic viruses can be genetically engineered to function as therapeutic cancer vaccines and can effectively eliminate infected as well as uninfected cancer cells without harming normal tissues [64,65] . Despite promising antitumor activity observed in animal models, the clinical integration of cancer vaccines thus far has been limited. A review of clinical trials employing therapeutic cancer vaccines from 1995 to 2004 concluded that over 96% of patients did not show objective evidence of cancer regression and often a very delayed immune response [66] . There were several obstacles that limited clinical activity of therapeutic cancer vaccines. Cancer vaccines are unable to generate sufficient number of circulating immune cells with high avidity for tumor recognition. In the case of solid tumors, the absence of costimulatory molecules and the lack of an inflammatory environment prevent the activation of T cells at the tumor site. To overcome these challenges, many strategies have been suggested to improve the efficacy of cancer vaccines [67] . One approach is to combine a cancer vaccine with a com-

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy 

pound that reverses the inactivation of the virus promoter, which drives the expression of a gene encoded by a DNA vaccine (Figure 2) . Since transcriptional silencing is associated with HDAC-mediated chromatin condensation, HDAC inhibitors have been reported to influence virus promoter-driven gene expression following DNA vaccination. AR-42 (also known as OSUHDAC42; ApexBio), a hydroxamate-tethered phenylbutyrate derivative that acts as a pan-HDAC inhibitor, increased the expression of Her-2/neu DNA vaccine and resulted in a greater infiltration of lymphocytes into tumors in mice [68] . HDAC inhibition enhanced antitumor response induced by Her-2/neu DNA vaccine, leading to significant delays in tumor progression and extending the lifespan of these mice. Similarly, AR-42 improved potency of therapeutic human papillomavirus (HPV) DNA vaccines by activating HPV antigen-specific CD8+ T cells and increasing the cell surface expression of MHC class I molecules on tumor cells  [69] . These works suggest that co-administration of HDAC inhibitors can overcome the obstacles confronting cancer vaccine therapy and boost its potency by augmenting tumor-specific immunity. Additionally, combinatorial activity of HDAC inhibitors and oncolytic viruses has been well studied and documented. HDAC inhibitors have been

used in conjunction with oncolytic virotherapy to transiently suppress innate immunity and promote infection of oncolytic viruses [70] . It has been demonstrated that a short-term exposure to an immunosuppressive agent is sufficient to abrogate inactivation of an antiviral response during oncolytic virus therapy of brain tumors [71] . HDAC inhibitors are also known to interfere with the ability of cells to induce IFNstimulated transcription and innate antiviral response, making them attractive agents for improving the efficacy of oncolytic virotherapy [72,73] . In support of this idea, when oncolytic viruses were supplemented with entinostat or vorinostat, this dampened cellular IFN response and resulted in robust viral protein production  [74] . Importantly, HDAC inhibitors- induced virus replication and apoptosis were specific to tumor tissue and were not observed in normal tissue samples. Similarly, pretreatment with valproic acid inhibited IFN responses and improved propagation and therapeutic efficacy of oncolytic herpes simplex virus in a human glioma xenograft model [75] . The timing of HDAC inhibitor treatment appears to be critical for counteracting IFN-mediated inhibition of viral propagation in tumor cells. Viral DNA replication was only enhanced when valproic acid was pre-administered for 14 h before being infected. The importance of HDAC

Enhancing the transcriptional activity of the viral promoter

Increasing antigen-specific T cells

Her2 DNA vaccine

E7

Her2 HDACi CMV Her2

Review

CMV Her2

Tumor cell

E7 DNA vaccine

HDACi

T cell

Depleting Treg and B cells

Oncolytic virus HDACi B cells

Treg cells Figure 2. Proposed mechanisms by which histone deacetylase inhibitors and cancer vaccines work together to sustain tumor regression. HDACi: Histone deacetylase inhibitor.

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Review  Park, Thomas & Munster inhibitor treatment schedule is further described in a recent study that showed a schedule-dependent boost in the oncolytic viral replication of vesicular stomatitis virus induced by entinostat, resulting in enhanced antitumor activity in a mouse melanoma model [40] . The presence of entinostat at the time of the oncolytic booster vaccine was associated with significant and selective depletion of Treg and B cells and an increase in cytotoxic T cells. Entinostat also abrogated the induction of neutralizing antibodies against the vesicular stomatitis virus. The differential regulation of lymphocytes resulted in reduced toxicity and improved the therapeutic window. The observed therapeutic effects were attenuated when entinostat was administered with the adenoviral vaccine at the priming step, and entinostat alone had no effect on the antitumor activity. The effects of schedule and HDAC inhibitor class may require further investigation to optimally integrate HDAC inhibitors into clinical testing. Identification of agents that can overcome host innate immune response against oncolytic virus or improve the therapeutic efficacy of the virus is of great interest. Several groups have reported that HDAC inhibitors can reduce IFN activity in tumor cells and allow replication and propagation of oncolytic virus. The ability of HDAC inhibitors to enhance the efficacy of viral therapy illustrates their value in future clinical trials. HDAC inhibitors & adoptive cell therapy

Adoptive T-cell transfer therapy involves expansion and reinfusion of autologous T cells that are genetically modified to more effectively attack their tumors. Thus far, adoptive cell therapy studies have been more encouraging than those on cancer vaccines. In fact, immunotherapy using T cells has been highly effective in treating metastatic melanoma [76] . Two major sources of activated, antigen-specific T cells are used for adoptive cell therapy: tumor-infiltrating lymphocytes (TILs) from resected metastatic tumors that have been expanded ex vivo with IL-2 and peripheral blood mononuclear cells that have been manipulated to enrich for tumor antigen-specific T cells [61] . The most widely used approaches in clinical testing involve activating blood-derived T cells with tumor antigens, transducing T cells with high-affinity T-cell receptor (TCR) that recognizes a specific tumor antigen, or transducing with a chimeric antigen receptor (CAR) that has been artificially constructed to contain the tumor antigen-binding domain of an antibody fused with a T-cell signaling domain. The advantage of transducing with TCRs or CARs is that T cells can be genetically engineered to express intracellular signaling domains of powerful T-cell molecules, like CD28, which results in recognition of cancer antigens with high avidity.

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TCR-T cells require a specific HLA subtype while HLA restriction is not required for CAR-T cells. While adoptive cell transfer has shown great promise in leukemia and select solid tumors, the complexity of the approach and its toxicities have rendered this therapy still investigational. To improve the therapeutic window of adoptive cell transfer and the use against a wider range of tumor types, combination approaches have been explored to elicit synergistic antitumor effect while limiting its toxicity. The use of HDAC inhibitors to sensitize tumors to immune-mediated cell death prior to adoptive cell therapy has been proposed based on the principle that co-administration of HDAC inhibitors reverses aberrant transcriptional regulation of pro-apoptotic factors (e.g., BMF) or prosurvival factors (e.g., BFL-1) in cancer cells [77] and enhances its responsiveness to adoptive cell therapy (Figure 3) . The potential use of HDAC inhibitors as an adjunct to adoptive cell transfer has been described in several preclinical studies. Romidepsin treatment and subsequent adoptive transfer of gp100 tumor-associated antigen-specific Pmel T cells enhanced T cell-mediated killing of B16/F10 murine melanoma cells and dramatically inhibited tumor growth compared with either T-cell transfer alone or romidepsin treatment alone [78] . Similarly, the adjunctive use of panobinostat with gp100-specific T-cell immunotherapy decreased tumor burden while creating a pro-inflammatory environment in an in vivo B16 murine melanoma model  [79] . This was accompanied by an increase in expansion and retention of gp100-specific Pmel T cells and a decrease in Treg cell population. As it has been demonstrated that Treg cell levels are negatively associated with clinical response to adoptive cell therapy in cancer [80] , HDAC inhibitors are attractive pharmacological agents that can be employed to modulate T effector function and Treg cell population levels. HDAC inhibitors have also been used to boost the CAR response of genetically modified T cells. Pretreatment with valproic acid enhanced the adoptive transfer of T cells expressing a CAR containing the extracellular domain of the NKG2D receptor and the intracellular domains of CD137 and CD3ζ in ovarian cancer cells [81] . Valproic acid selectively sensitized cancer cells to T-cell attack by inducing NKG2D ligand surface expression and improving antigen-specific recognition of NKG2D CAR-expressing T cells. Although the combination of HDAC inhibitors and adoptive transfer of CAR-expressing T cells seems promising, the concerns around the auto-immune toxicity and long-term sequelae need to be better addressed prior to the clinical introduction of HDAC inhibitor induced priming of CAR T cells.

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy 

Increasing expression of tumor-specific ligand that can be recognized by T-cell receptor T cells

Creating a pro-apoptotic environment Tumor-specific ligand Pro-apoptotic factors

Review

HDACi

Tumor cell

HDACi

T cell receptor

Pro-survival factors

T cells with high-affinity T cell receptor Increasing expression of tumor-specific ligand that can be recognized by chimeric antigen receptor T cells

Creating a pro-inflammatory environment

Tumor-specific ligand

Cytokines (TNF, IFN-γ)

HDACi

HDACi

Treg cells

Tumor cell

Chimeric antigen receptor

CD8+ T cells

Chimeric antigen receptor-expressing T cell Figure 3. Proposed mechanisms by which histone deacetylase inhibitors and adoptive cell therapy elicit a synergistic antitumor effect. HDACi: Histone deacetylase inhibitor.

HDAC inhibitors & immune checkpoint inhibitors

The immune system is tightly controlled by signals transmitted through stimulatory and inhibitory receptors (Figure 4A) . These receptors serve as checkpoints to maintain self-tolerance and minimize tissue damage from dysregulated immune reaction. CTLA4 and PD-1 are both inhibitory receptors that counterbalance immune activation. While CTLA4 functions as a negative regulator of T-cell activation, PD-1 limits T-cell effector activity [82] . Tumor cells manipulate the expression of immune checkpoint proteins as a mechanism of immune resistance. For instance, tumor cells upregulate the expression of PD-1 ligands in order to evade a T-cell response [83] . Major advances in recent cancer therapy have come from the introduction of immune checkpoint inhibitors in historically difficult-to-treat tumors, such as melanoma, lung cancer and kidney cancer. Immune checkpoint inhibitors block the inter-

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action between an inhibitory receptor on a lymphocyte and its ligand on an antigen presenting cell, instead of directly targeting the tumor cells (Figure 4B) . Pharmacological inhibition of CTLA4, PD-1 and PD-L1 has shown prolonged antitumor activity against a large range of tumors. The anti-CTLA4 mAb, ipilimumab, was the first monoclonal antibody to receive approval by the US FDA in 2011 for the treatment of advanced melanoma. The anti-PD-1 antibodies, pembrolizumab and nivolumab, were granted accelerated approval in September and December 2014, respectively, for treatment of advanced melanoma. A recent study examined the effect of these two immune checkpoint inhibitors, anti-PD-1 and anti-CTLA4 antibodies, in conjunction with two epigenetic-modulating drugs, entinostat and 5-azacytidine (DNMT inhibitor), in mice bearing colorectal carcinoma CT26 tumor or metastatic mammary 4T1 tumor [84] . Both types of tumors responded well to the combination regimen: pri-

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Cancer cell

HDACi

Antigen

MHC

TCR

T cell

Cancer cell T cell

PD-L1 (-) PD-L1

(-)

Immune response inhibition

(-) CD28

CTLA4

-1 PD b ma izu rol ab mb lum Pe nivo or

-1

PD

(+)

B7

CTLA4 Ipilimumab

PD-L1/PD-L2

B7

PD-L1/PD-L2

Antigenpresenting cell

Myeloid-derived suppressor cells

Antigenpresenting cell

Figure 4. Proposed mechanisms by which histone deacetylase inhibitors and immune checkpoint inhibitors overcome resistance and re-sensitize drug-resistant tumor cells. (A) T cell interacting with antigen presenting cell and cancer cell. (B) Immune response inhibition being blocked by immune checkpoint inhibitors, such as pembrolizumab and ipilimumab.

mary tumors were eradicated in 10/11 mice with CT26 tumors and in all ten mice with 4T1 tumors. Mechanistic studies revealed that myeloid-derived suppressor cells are responsible for immunosuppressive activities in the tumor. Interestingly, the primary tumors and metastases were not found in any of the mice treated with both antibodies plus entinostat, whereas the primary tumors, but no metastases, were observed in the mice treated with both antibodies plus 5-azacytidine. These data suggest that epigenetic modulation, especially by HDAC inhibitors, may significantly impact tumor regression at both primary and metastatic sites. This addition may be of considerable consequence in clinical use since tumor regression in patients is often delayed or limited. Further studies are needed to determine whether these effects are dependent on select HDAC inhibitor class.

Clinical evidence of synergistic activities of HDAC inhibitors & immune checkpoint inhibitors Clinically, epigenetic modulation with both 5-azacytidine and entinostat has resulted in antitumor responses in a small number of heavily pretreated patients with metastatic NSCLC [85] . Of the 42 patients enrolled in this study, one patient had a complete response that lasted 14 months and a second patient had a partial response without disease progression for 2 years after completing protocol therapy. Furthermore, preclinical work with NSCLC cell lines demonstrated that 5-azacytidine can prime lung cancer cells to PD-1 inhibitors [86] . The durable responses seen in the initial trial and the observation that supports the benefit of epigenetic priming in immune checkpoint therapy have prompted a new clini-

Table 1. Current clinical trials combining a histone deacetylase inhibitor and immune checkpoint inhibitor in various cancer types. ClinicalTrials identifier

Status

Phase

Cancer type

HDAC inhibitor

Immune checkpoint inhibitors

Additional intervention

Ref.

NCT02032810

Recruiting

I

Unresectable III/IV melanoma

Panobinostat

Ipilimumab (anti-CTLA4)

 

[87] 

NCT01928576

Recruiting

II

Non-small-lung cancer

Entinostat

Nivolumab (anti-PD-1)

Azacitidine

[88] 

NCT02395627

Recruiting

II

ER + hormone therapyresistant breast cancer

Vorinostat

Pembrolizumab (anti-PD-1)

Tamoxifen

  [89]

HDAC: Histone deacetylase.

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy 

cal trial that evaluates potential sensitization to PD-1 blockade after epigenetic therapy (Table 1). There is no published data yet on the clinical efficacy of immune checkpoint blockers, like anti-CTLA4 antibody and anti-PD-1 antibody, in combination with HDAC inhibitors. A few Phase I and II clinical trials are currently recruiting patients to evaluate HDAC inhibitors in combination with immune checkpoint inhibitors in several cancer types (Table 1). One trial in particular is investigating the safety and efficacy of vorinostat, tamoxifen and pembrolizumab in hormone receptor expressing advanced breast cancer. The goal of this trial is to test the potential of epigenetic immune priming in reversing hormone therapy resistance in pre- and postmenopausal women with breast cancer. The backdrop for this study comes from the observation that PD-L1 expression is upregulated in breast cancer compared with normal breast tissue, implying that PD-1 may have a role in breast cancer [90] . It is hypothesized that immune priming with vorinostat may break the immune tolerance and increase the efficacy of the PD-1 inhibitor pembrolizumab, because it has previously been reported that HDAC inhibitors can impair the suppressive function of Treg populations in cancer cells [41] . To define the optimal approach for epigenetic immune priming in hormone refractory breast cancer, patients will be randomized into two arms: sequential priming with optional immune activation versus concurrent priming with maximal dosing of both epigenetic and immune modulators. Patients will be assessed for objective response by RECIST criteria. The FDA approval of anti-CTLA4 and anti-PD-1 therapy will continue to raise the awareness of the potential anti­tumor activity of the immune system in cancer therapy. This will most likely lead to additional clinical studies that will explore immune checkpoint inhibitors in combination with current cancer treatment. Conclusion Accumulating evidence indicates that epigenetic alterations cause aberrant patterns of gene expression in

Review

cancer, implicating the potential of HDAC inhibitors to restore proper expression in tumor cells. The recent advances in immunotherapy, including adoptive T-cell transfer and the pharmacological inhibition of CTLA4 and PD-1, have clinically validated the role of immune dysfunction in cancer. The increasing understanding of emerging therapy resistance through epigenetic adaptation suggests an important role of epigenetic modulators in conjunction with immunotherapy. Future perspective Epigenetic modulation by HDAC inhibitors combined with immunotherapy may result in a two-step improvement. First, cancer cells are treated with HDAC inhibitors to increase sensitivity to recognition and attack by T cells. Once primed, effector T cells exhibit enhanced functionality and demonstrate synergistic antitumor activity. Furthermore, the differential effect on effector T cells with a global downregulation of naiive T cells, B cells and myelocytes may reduce the activation of destructive auto-immunity and the development of neutralizing antibodies. Taken together, pretreatment with HDAC inhibitors sensitizes tumor cells to successive immunotherapeutic approaches, resulting in tumor suppression and induction of long-lasting response. The future of cancer therapy includes the exploration of various combinations of HDAC inhibitors and immunotherapy. The interest in the development of antibodies targeting either CTLA4 or PD-1 will continue to propel this exciting, but challenging, area of cancer immunotherapy. We anticipate the results of preclinical studies and clinical trials involving HDAC inhibitors and anticancer mAbs, especially those that serve as immune checkpoint blockers, in the near future. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment,

Executive summary • Histone deacetylase (HDAC) inhibitors are approved as anticancer agents in cutaneous T-cell lymphoma and reverse therapy resistance in solid tumors. • HDAC inhibitors can improve the potency of cancer vaccines by reversing the inactivation of the virus promoter or by suppressing the antiviral immune response to promote replication and virus-induced apoptosis. • HDAC inhibitors can enhance its responsiveness to adoptive cell therapy by creating a pro-inflammatory environment or by inducing the expression of tumor-specific ligand that can be recognized by T cells. • Monoclonal antibodies that block immune checkpoints without directly targeting tumor cells have recently been approved for the treatment of melanoma and show great promise in many other solid tumors and hematological malignancies. • HDAC inhibitors have the potential to sensitize tumor cells to immune-related destruction and differentially modulate T and B cells as well as other immune-relevant myeloid cells. Hence, immune priming may improve immunotherapy and reduce auto-immune mediated side effects.

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No writing assistance was utilized in the production of this manuscript.

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Bolden JE, Peart MJ, Johnstone RW. Anticancer activities of histone deacetylase inhibitors. Nat. Rev. Drug Discov. 5(9), 769–784 (2006).

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Muller BM, Jana L, Kasajima A et al. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer – overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer 13, 215 (2013).

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Weichert W, Roske A, Gekeler V et al. Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy 

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Bridle BW, Chen L, Lemay CG et al. HDAC inhibition suppresses primary immune responses, enhances secondary immune responses, and abrogates autoimmunity during tumor immunotherapy. Mol. Ther. 21(4), 887–894 (2013).

••

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Zhang H, Xiao Y, Zhu Z, Li B, Greene MI. Immune regulation by histone deacetylases: a focus on the alteration of FOXP3 activity. Immunol. Cell Biol. 90(1), 95–100 (2012).

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Russell SJ, Peng KW, Bell JC. Oncolytic virotherapy. Nat. Biotechnol. 30(7), 658–670 (2012).

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Authors show that HDAC inhibitor depsipeptide (FK228) enhances gp100 antigen expression and promote tumor-specific T-cell-mediated killing of melanoma cells.

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Lisiero DN, Soto H, Everson RG, Liau LM, Prins RM. The histone deacetylase inhibitor, LBH589, promotes the systemic cytokine and effector responses of adoptively transferred CD8+ T cells. J. Immunother. Cancer 2, 8 (2014).

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Lee SY, Huang Z, Kang TH et al. Histone deacetylase inhibitor AR-42 enhances E7-specific CD8(+) T cellmediated antitumor immunity induced by therapeutic HPV DNA vaccination. J. Mol. Med. 91(10), 1221–1231 (2013).

Song DG, Ye Q, Santoro S, Fang C, Best A, Powell DJ Jr. Chimeric NKG2D CAR-expressing T cell-mediated attack of human ovarian cancer is enhanced by histone deacetylase inhibition. Hum. Gene Ther. 24(3), 295–305 (2013).

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••

Authors report that cotreatment with epigeneticmodulating drugs (histone deacetylase inhibitor entinostat and DNA methyltransferase inhibitor 5-azacytidine) and immune check-point inhibitors (anti-PD-1 and antiCTLA4 antibodies) cured more than 80% of the tumorbearing mice by eliminating myeloid-derived suppressor cells

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Authors demonstrate that HDAC inhibitors can be utilized to regulate cellular innate antiviral response and allow growth of therapeutic viruses within tumors.

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Murakami T, Sato A, Chun NA et al. Transcriptional modulation using HDACi depsipeptide promotes immune

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Epigenetic modulation with histone deacetylase inhibitors in combination with immunotherapy.

Understanding the contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides the rationale for the use of ep...
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