Overcoming Immune Checkpoint Blockade Resistance via EZH2 Inhibition

Kim, Hye-Jung; Cantor, Harvey; Cosmopoulos, Kat

doi:10.1016/j.it.2020.08.010

Cited by 53 publications

(39 citation statements)

References 99 publications

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“…Epigenetic modulators can also directly modulate tumor-infiltrating immune cells [ 43 ]. Inhibition of EZH2 has been reported to be linked with enhanced NK and T cell effector activities in certain cancers [ 25 ], as well as with an increased expansion of myeloid-derived suppressor cells (MDSCs) and consequent suppression of antitumor immunity [ 44 ].…”

Section: Resultsmentioning

confidence: 99%

“…EZH2-dependent chromatin remodeling also directly shapes immune cell fate and functions [ 25 ]. However, understanding the overall impact of EZH2 inhibition on antitumor immunity requires consideration of its pleiotropic effects on different types of immune and tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…Beyond the direct antiproliferative effect on tumor cells, EPZ-6438-driven epigenetic reprogramming can both directly and indirectly affect the tumor microenvironment (TME). Accumulating evidence highlights the importance of EZH2 in promoting cancer cell immune escape in different types of malignancies [ 23 , 24 ] and in shaping different tumor-infiltrating immune cells, overall supporting both immunosuppressive activities and antitumor immunity [ 25 ]. Thus far, the impact of EZH2 inhibition on human tumor-associated macrophages (TAMs) accumulation and functional activation is still largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids

Mola

Pinton

Erreni

et al. 2021

IJMS

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Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with a long latency period and dismal prognosis. Recently, tazemetostat (EPZ-6438), an inhibitor of the histone methyltransferase EZH2, has entered clinical trials due to the antiproliferative effects reported on MPM cells. However, the direct and indirect effects of epigenetic reprogramming on the tumor microenvironment are hitherto unexplored. To investigate the impact of tumor-associated macrophages (TAMs) on MPM cell responsiveness to tazemetostat, we developed a three-dimensional MPM spheroid model that recapitulates in vitro, both monocytes’ recruitment in tumors and their functional differentiation toward a TAM-like phenotype (Mo-TAMs). Along with an increased expression of genes for monocyte chemoattractants, inhibitory immune checkpoints, immunosuppressive and M2-like molecules, Mo-TAMs promote tumor cell proliferation and spreading. Prolonged treatment of MPM spheroids with tazemetostat enhances both the recruitment of Mo-TAMs and the expression of their protumor phenotype. Therefore, Mo-TAMs profoundly suppress the antiproliferative effects due to EZH2 inhibition in MPM cells. Overall, our findings indicate that TAMs are a driving force for MPM growth, progression, and resistance to tazemetostat; therefore, strategies of TAM depletion might be evaluated to improve the therapeutic efficacy of pharmacological inhibition of EZH2.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids

Mola

Pinton

Erreni

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…First, through spearman correlation analysis, EZH2, KIF18B and EME1 were identi ed as the three genes most positively associated with RAD54L expression, and ssGSEA algorithm revealed strong correlations of RAD54L and the three most coexpressed genes with immune in ltration. Interestingly, accumulating evidence have demonstrated that EZH2 is a potential therapeutic target associated with immunotherapy resistance [42][43][44], which exhibited the strongest expression correlation with RAD54L in ccRCC. Additionally, given the generalizability of immune response in tumors, xCell and ssGSEA algorithm was combined to explored the correlations of RAD54L expression with the immune cell across more than 30 cancer types.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive Analysis of DNA Damage Repair Genes and Identification of RAD54L as an Immunological and Prognostic Biomarker in Clear Cell Renal Cell Carcinoma and Other Cancers

Wang¹,

Yang²,

Yi³

et al. 2021

Preprint

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Background: DNA damage repair (DDR) plays a pivotal role in the tumorigenesis and progression of multiple cancers, including clear cell renal cell carcinoma (ccRCC), and immunotherapy is galvanizing research on ccRCC, while the interactions between DDR and tumor microenvironment (TME) in ccRCC still remain elusive. Methods: The expression, mutation and clinical data were downloaded from public datasets in TCGA, GTEx and human protein atlas (HPA) database. Consensus clustering analysis was used to cluster subtypes based upon the expression of DDR genes. Cox regression analysis was adopted to conduct survival analysis, and qRT-PCR method was used to verify the expression of RAD54L in ccRCC samples. GSEA was employed to explore potential enriched KEGG pathways. CIBERSORT, ssGSEA and xCell algorithms were used to evaluate the tumor microenvironment (TME).Results: Two subtypes were identified according to the expression of DDR genes in ccRCC. Subtype1 was correlated with increased proportion of higher-grade tumors, worse prognosis and lower PD-L1 expression compared to subtype2. Distinct TME was also noted between two subtypes. GSEA revealed that the TGF-β signaling pathway was significantly enriched in subtype1. RAD54L was subsequently determined as a potential immune-related DDR gene, which was positively associated with PD-L1 expression and its elevated expression predicted unfavorable prognosis in ccRCC. qRT-PCR also verified the overexpression of RAD54L in ccRCC samples. Additionally, a systematic analysis involving 33 cancer types demonstrated that RAD54L was remarkably upregulated and its overexpression tightly linked to worse prognosis in multiple cancers. Moreover, both xCell and ssGSEA algorithm showed the strong associations between RAD54L expression and immune infiltration in more than 30 cancers. Conclusions: DDR is implicated in regulating TME of ccRCC, and RAD54L is a potential immunological and prognostic biomarker in multiple types of cancer, including ccRCC.

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“…The loss of MHC II expression impairs the antigen presentation, resulting in TAM-induced immunosuppression ( 82 ). The differentiation and polarization of macrophages can also be modulated by the enhancer of zeste homolog 2 (EZH2) ( 83 ), a histone methyltransferase and the catalytic subunit of polycomb repressive complex 2 (PRC2), indicating that EZH2 is involved in the reshaping of TIME.…”

Section: Reprograming Of Immune Cells In Timementioning

confidence: 99%

Role of Epigenetic Regulation in Plasticity of Tumor Immune Microenvironment

Yang

Wang

2021

Front. Immunol.

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The tumor immune microenvironment (TIME), an immunosuppressive niche, plays a pivotal role in contributing to the development, progression, and immune escape of various types of cancer. Compelling evidence highlights the feasibility of cancer therapy targeting the plasticity of TIME as a strategy to retrain the immunosuppressive immune cells, including innate immune cells and T cells. Epigenetic alterations, such as DNA methylation, histone post-translational modifications, and noncoding RNA-mediated regulation, regulate the expression of many human genes and have been reported to be accurate in the reprogramming of TIME according to vast majority of published results. Recently, mounting evidence has shown that the gut microbiome can also influence the colorectal cancer and even extraintestinal tumors via metabolites or microbiota-derived molecules. A tumor is a kind of heterogeneous disease with specificity in time and space, which is not only dependent on genetic regulation, but also regulated by epigenetics. This review summarizes the reprogramming of immune cells by epigenetic modifications in TIME and surveys the recent progress in epigenetic-based cancer clinical therapeutic approaches. We also discuss the ongoing studies and future areas of research that benefits to cancer eradication.

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Overcoming Immune Checkpoint Blockade Resistance via EZH2 Inhibition

Cited by 53 publications

References 99 publications

Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids

Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids

Comprehensive Analysis of DNA Damage Repair Genes and Identification of RAD54L as an Immunological and Prognostic Biomarker in Clear Cell Renal Cell Carcinoma and Other Cancers

Role of Epigenetic Regulation in Plasticity of Tumor Immune Microenvironment

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