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
View: Text | PDF
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

×

Figure 8

Intratumoral injection of heat-iMVA sensitizes PRC2-loss tumors to anti–PD-1 and anti-CTLA4 therapies in murine cancer models.

Options: View larger image (or click on image) Download as PowerPoint
Intratumoral injection of heat-iMVA sensitizes PRC2-loss tumors to anti–...
(A and B) Fold changes in mRNA expression levels of type I IFN (A) and IFN-γ–responsive (B) genes by qRT-PCR, 24 hours after heat-iMVA infection in vitro (n = 3). (C) Schematic of the treatment plan for heat-iMVA and ICB therapy in PRC2-loss AT3 (sgEed) or SKP605 (sgEed) tumors. (D and E) Tumor growth curves (D) and Kaplan-Meier survival curves (E) over time in mice with AT3 sgEed tumors under the indicated treatment conditions (n = 10 per cohort). (F) Percentages and representative FACS profiles of tumor-infiltrating CD45+ immune cells in AT3 (sgEed) tumors under the indicated treatment conditions (n = 5 per cohort). (G) Percentages of CD4+ and CD8+ T cells among all live cells and the relative Ki67+ subpopulation in AT3 (sgEed) tumors under the indicated treatment conditions. (H and I) Percentages of FoxP3+ Tregs among CD4+ T cells (H) and GzmB+ cells among CD8+ T cells (I) in AT3 (sgEed) tumors under the indicated treatment conditions (n = 5 per cohort). (J and K) Tumor growth curves for each tumor (J) and Kaplan-Meier survival curves (K) over time for mice with SKP605 (sgEed) tumors under the indicated treatment conditions. SKP605 sgEed cells were s.c. grafted onto the right flank of C57BL/6J mice (n = 8–10 tumors per cohort). (L) Tumor growth curves for each tumor s.c. grafted onto the left flank of C57BL/6J mice (n = 7–10 tumors per cohort). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired, 2-tailed t test (D and G–I) between 2 groups; by log-rank (Mantel-Cox) test (E and K); and by 1-way ANOVA (G–I) among 3 groups. Data indicate the mean ± SEM.