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 6

PRC2 loss leads to an antigen presentation defect and recapitulates the immune evasion phenotype in a murine mammary tumor syngeneic transplantation model.

Options: View larger image (or click on image) Download as PowerPoint
PRC2 loss leads to an antigen presentation defect and recapitulates the ...
(A) Schematic of the in vivo experimental and analysis plan for murine AT3 mammary tumors. (B) Growth curves of PRC2-isogeneic (sgCon vs. sgEed) AT3 syngeneic transplant tumors over time (n = 9–10 tumors per cohort). (C) Immunoblots of H3K27me3 in pre-graft AT3 cells and explanted AT3 tumors. (D) Heatmap of expression changes of genes related to antigen presentation, IFN-γ signaling responses, chemokines, and WNT signaling from RNA-Seq of AT3 tumors. (E and F) Percentage of total CD45+ immune cells (E) and subpopulations (F) of total live cells in PRC2-isogenic AT3 syngeneic grafted tumors (n = 5 tumors per cohort). (G) Percentage of IFN-γ+ cells among total CD4+ and CD8+ T cells in PRC2-isogenic AT3 tumors (n = 10 tumors per cohort). (H) Tetramer staining of OVA-specific CD8+ T cells in TdLNs 14 days after transplanting PRC2-isogenic AT3 cells into C57BL/6J mice. TdLNs for OVA+ tumors: n = 4; TdLNs for OVA– sgCon tumors: n = 3 pooled from 2 independent experiments. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 1-way ANOVA (B and E–G), with correction for multiple comparisons by 2-stage linear step-up method of Benjamini, Krieger, and Yekutieli (H) (FDR q < 0.05 was significant). Data indicate the mean ± SEM.