@article{6098cf163d1b4225b6a5ea2ba9c104ac,
title = "Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses",
abstract = "(Figure presented) 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.",
author = "Juan Yan and Yuedan Chen and Patel, {Amish J.} and Sarah Warda and Lee, {Cindy J.} and Nixon, {Briana G.} and Wong, {Elissa W.P.} and Miranda-Rom{\'a}n, {Miguel A.} and Ning Yang and Yi Wang and Pachai, {Mohini R.} and Jessica Sher and Emily Giff and Fanying Tang and Ekta Khurana and Sam Singer and Yang Liu and Galbo, {Phillip M.} and Maag, {Jesper L.V.} and Koche, {Richard P.} and Deyou Zheng and Antonescu, {Cristina R.} and Liang Deng and Li, {Ming O.} and Yu Chen and Ping Chi",
note = "Funding Information: We thank all members of the Chi and Chen laboratory for general support. We also thank William Gerald and Leon (Xiaoliang) Xu for the patient-derived MPNST M3 cell line. Next-generation sequencing, ChIP-Seq, CUT&RUN, RNA-Seq, and ATAC-Seq were performed at the IGO/Center for Molecular Oncology and Center for Epigenetics Research. IHC of FFPE and MPNST samples were procured from and performed at the Pathology core facility, and animal studies were performed at the Center for Comparative Medicine and Pathology core facility at MSK. This work was supported by grants from the NIH and the National Cancer Institute (NCI) (R01 CA228216, DP2 CA174499); Department of Defense (DOD) grant W81XWH-15-1-0124; a Francis Collins Scholar NTAP grant; a grant from the Cycle for Survival and Linn Family Discovery Fund (to PC); NCI, NIH grant P50 CA217694 (to PC, SS, and CRA); NCI, NIH grant R01 CA208100 (to Yu Chen); a grant from the Geoffrey Beene Cancer Research Fund (to PC, MOL, and LD); Translational Oncology Research in Oncology Training Program T32 grant 5T32CA160001-09 (to AJP); and NIH grant P30 CA 008748 to the MSK Cancer Center (Core Grant). Publisher Copyright: {\textcopyright} 2022, Yan et al.",
year = "2022",
month = sep,
day = "1",
doi = "10.1172/JCI153437",
language = "English (US)",
volume = "132",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "17",
}
