Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses
Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Cindy J. Lee, Briana G. Nixon, Elissa W.P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Mohini R. Pachai, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo Jr., Jesper L.V. Maag, Richard P. Koche, Deyou Zheng, Cristina R. Antonescu, Liang Deng, Ming O. Li, Yu Chen, Ping Chi
Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Cindy J. Lee, Briana G. Nixon, Elissa W.P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Mohini R. Pachai, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo Jr., Jesper L.V. Maag, Richard P. Koche, Deyou Zheng, Cristina R. Antonescu, Liang Deng, Ming O. Li, Yu Chen, Ping Chi
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Research Article Oncology

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses

Abstract

Immune checkpoint blockade (ICB) has demonstrated clinical success in “inflamed” tumors with substantial T cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell–intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrated that inactivation of the polycomb-repressive complex 2 (PRC2) core components embryonic ectoderm development (EED) or suppressor of zeste 12 homolog (SUZ12), a prevalent genetic event in malignant peripheral nerve sheath tumors (MPNSTs) and sporadically in other cancers, drove a context-dependent immune-desert TME. PRC2 inactivation reprogramed the chromatin landscape that led to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., IFN-γ signaling) to PRC2-regulated developmental and cellular differentiation transcriptional programs. Further, PRC2 inactivation led to diminished tumor immune infiltrates through reduced chemokine production and impaired antigen presentation and T cell priming, resulting in primary resistance to ICB. Intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) enhanced tumor immune infiltrates and sensitized PRC2-loss tumors to ICB. Our results identify molecular mechanisms of PRC2 inactivation–mediated, context-dependent epigenetic reprogramming that underline the immune-desert phenotype in cancer. Our studies also point to intratumoral delivery of immunogenic viruses as an initial therapeutic strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

Authors

Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Cindy J. Lee, Briana G. Nixon, Elissa W.P. Wong, Miguel A. Miranda-Román, Ning Yang, Yi Wang, Mohini R. Pachai, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo Jr., Jesper L.V. Maag, Richard P. Koche, Deyou Zheng, Cristina R. Antonescu, Liang Deng, Ming O. Li, Yu Chen, Ping Chi

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Figure 7

PRC2-loss tumors confer primary resistance to ICB therapies.

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PRC2-loss tumors confer primary resistance to ICB therapies. (A) Schemat...
(A) Schematic of the plan for treatment of PRC2-loss AT3 tumors with ICB therapy. (B) Tumor growth curves of PRC2-isogenic AT3 tumors with ICB and control treatments over time (n = 10 tumors per cohort). (C) Percentage of CD45+ tumor immune cells among all live cells in PRC2-isogneic AT3 tumors and spleens (n = 5 per cohort). (D) Representative examples of CD45+ cells (gated CD45+ cells among all live cells) by FACS for C. (E) Percentage of T cells in PRC2-isogenic AT3 tumors treated with ICB and controls (n = 5 per cohort). (F) Representative examples of T cells (gated TCRβ+ in CD45+ cells) by FACS for E. (G) Percentage of IFN-γ+, CD4+, and CD8+ T cells among all live cells in tumors (n = 5 per cohort). (H) Growth curves of AT3 sgCon tumors with the indicated treatment over time (n = 6–10 tumors per cohort). (I) Relative mRNA Ifng expression changes by qRT-PCR in tumors from H, normalized to the anti-2A3 (α2A3) control treatment condition (n = 4 tumors per cohort). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA corrected for multiple comparisons by the 2-stage, linear step-up method of Benjamini, Krieger, and Yekutieli (FDR q < 0.05 was significant) (B, C, E, and G–I) compared with the ICB treatment group. Data indicate the mean ± SEM.