Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy

Goswami, Sangeeta; Apostolou, Irina; Zhang, Jan; Skepner, Jill; Anandhan, Swetha; Zhang, Xuejun; Xiong, Liangwen; Trojer, Patrick; Aparicio, Ana; Subudhi, Sumit K.; Allison, James P.; Zhao, Hao; Sharma, Padmanee

doi:10.1172/jci99760

Cited by 192 publications

(184 citation statements)

References 21 publications

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“…For example, selectively blocking FAO or enhancing glycolysis may disrupt Treg stability while promoting anti‐tumour T‐cell function. Perhaps most remarkably, small molecule inhibitors of the chromatin modifier EZH2 may not only reprogramme TI‐Treg function, but also directly increase cytotoxic T‐cell activity and recruitment to the TME (by increasing Th1 chemokine production from tumour cells) . In other instances, targeting some of the pathways described here may have tempered effects due to blocking the function of beneficial immune cell populations attacking the cancer.…”

Section: Conclusion: Key Challenges and Next Stepsmentioning

confidence: 95%

“…Furthermore, anti‐CTLA4 checkpoint blockade dramatically increases EZH2 expression within the TME, presumably due to increased CD28 signalling, and may promote TI‐Treg suppressive activity. As a result, the combination of anti‐CTLA4 with EZH2 inhibition can act synergistically to engage potent anti‐cancer immunity in murine cancer models …”

Section: Transcription In Ti‐tregmentioning

confidence: 99%

“…Perhaps most remarkably, small molecule inhibitors of the chromatin modifier EZH2 may not only reprogramme TI-Treg function, but also directly increase cytotoxic T-cell activity and recruitment to the TME (by increasing Th1 chemokine production from tumour cells). 117,118,121,122 In other instances, targeting some of the pathways described here may have tempered effects due to blocking the function of beneficial immune cell populations attacking the cancer. For example, blocking CD28 can reprogramme Tregs, but CD28 is required for T-cell activation, the acquisition of glycolytic metabolism necessary for effector functions, and the efficacy of PD-1 checkpoint blockade therapy.…”

Section: Conclusion: Key Challenges and Next Stepsmentioning

confidence: 99%

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Treg programming and therapeutic reprogramming in cancer

Ayala

DuPage

2019

Immunology

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Summary Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T‐cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour‐infiltrating Tregs (TI‐Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI‐Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI‐Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T‐cells within tumours, we highlight mechanisms to selectively reprogramme TI‐Tregs for the treatment of cancer.

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Section: Conclusion: Key Challenges and Next Stepsmentioning

confidence: 95%

Section: Transcription In Ti‐tregmentioning

confidence: 99%

Section: Conclusion: Key Challenges and Next Stepsmentioning

confidence: 99%

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Treg programming and therapeutic reprogramming in cancer

Ayala

DuPage

2019

Immunology

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“…In fact, several epigenetic inhibitors, such as EZH2 and DNMT inhibitors have been shown to improve the efficacy of immunotherapy treatments such as anti-CTLA-4 and anti-PD1 treatment. For example, Goswami et al (2018) showed that modulation of EZH2 expression in T cells improves efficacy of anti-CTLA-4 therapy in vivo [49]. Similarly, the DNMT inhibitor decitabine enhanced lymphocyte migration and function and synergized with CTLA-4 blockade in a murine ovarian cancer model [50].…”

Section: Epitherapy and Combination Therapymentioning

confidence: 99%

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

et al. 2020

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Background: Cancer cells subvert natural immunosuppression by upregulating the expression of checkpoint proteins and their ligands. For example, tumor cells expressing programmed death-ligand 1 (PD-L1) induce immune cell tolerance to cancers, thereby facilitating tumor progression. The recent clinical success of immunotherapy, particularly checkpoint blockade, represents a significant advance in cancer therapy. However, many cancers develop resistance to immunotherapies, and the underlying mechanisms and how these might be exploited to overcome resistance still need to be determined.Methods: T cell dysfunction, in part caused by chronic T cell receptor stimulation, diminishes the capacity for durable responses to checkpoint blockade. Furthermore, T cell populations are phenotypically and functionally heterogeneous, resulting in varying responses to checkpoint blockade. Recent molecular studies of T cell heterogeneity have shown that checkpoint blockade on its own does not alter the epigenetic landscape of T cells, despite epigenetic changes governing T cell phenotype.Conclusion: Here we argue that epigenetic modifiers can be used to prime and sensitize T cells to immunotherapy. Administering epitherapy in conjunction with checkpoint blockade could decrease T cell exhaustion and immunotherapy resistance in many cancer types.

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“…EZH2 can negatively regulate interferon response genes, T helper cell (TH)-1 type chemokines, and major histocompatibility complex (MHC) expression in tumor cells [4,5]. EZH2 inhibition can enhance tumor immunogenicity through activation of endogenous retroviruses [6] and can modulate immune cell differentiation [7,8]. Therefore, it has been hypothesized that EZH2 inhibitors, which are currently part of clinical studies [9], can overcome resistance to ICB by targeting tumor cells and modulating the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade

et al. 2020

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Background: Upregulation of the histone methyltransferase enzyme EZH2 and its histone modification H3K27me3 has been linked to melanoma progression, metastasis, and resistance to immune checkpoint blockade (ICB). In clinical trials, EZH2 inhibitors are currently tested to overcome resistance to ICB. The aim of this study is to evaluate expression patterns and the predictive value of H3K27me3 and EZH2 in metastatic melanoma samples prior to ICB. As H3K27me3 expression has been associated with a dedifferentiated, invasive melanoma phenotype, we also investigated the prognostic value of H3K27me3 expression in primary melanomas. Results: H3K27me3 and EZH2 expression were evaluated in a cohort of 44 metastatic melanoma samples before ICB using immunohistochemistry (IHC). 29/44 (66%) of melanomas showed H3K27me3 expression, and 6/44 (14%) showed EZH2 expression. No predictive value for therapeutic response to anti-PD-1 therapy could be found for H3K27me3 or EZH2 expression on melanoma cells. To investigate the prognostic significance of H3K27me3, we analyzed H3K27me3 expression in a representative cohort of 136 primary melanomas with known sentinel lymph node status. H3K27me3 expression is associated with increased tumor thickness and nodal involvement. Melanoma metastases showed a higher expression of H3K27me3 in comparison to primary melanomas. In human melanoma cell lines, TNFα and INFγ could not induce H3K27me3 expression. Conclusion: Our study shows that H3K27me3 expression is more frequent than EZH2 and is associated with a more invasive and metastatic melanoma cell phenotype. We suggest that H3K27me3 expression by IHC might be a suitable method to evaluate the activity of EZH2 inhibitors in clinical trials.

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Modulation of EZH2 expression in T cells improves efficacy of anti–CTLA-4 therapy

Cited by 192 publications

References 21 publications

Treg programming and therapeutic reprogramming in cancer

Treg programming and therapeutic reprogramming in cancer

Epitherapy and immune checkpoint blockade: using epigenetic reinvigoration of exhausted and dysfunctional T cells to reimburse immunotherapy response

H3K27me3 and EZH2 expression in melanoma: relevance for melanoma progression and response to immune checkpoint blockade

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