Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses
Juan Yan, … , Yu Chen, Ping Chi
Juan Yan, … , Yu Chen, Ping Chi
Published July 19, 2022
Citation Information: J Clin Invest. 2022;132(17):e153437. https://doi.org/10.1172/JCI153437.
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Research Article Oncology Therapeutics

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 3

PRC2 loss reprograms the chromatin landscape and suppresses a subset of IFN-γ–responsive genes.

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PRC2 loss reprograms the chromatin landscape and suppresses a subset of ...
(A) Immunoblots of the indicated proteins in PRC2-isogenic human MPNST cells. (B) Volcano plot of chromatin accessibility changes by ATAC-Seq. Red dots represent markedly changed ATAC peaks (FDR q < 0.1, fold change ≥1.5). (C) Density plot of histone modifications by ChIP-Seq, centered on markedly increased (left) and decreased (right) ATAC peaks by SUZ12 knockout in M3 cells. Promoter: transcriptional start site (TSS) ± 2 kb; nonpromoter: rest of the genomic regions other than promoters, including distal regulatory enhancers and intergenic regions. (D) Distribution of differential H3K27ac peaks across different genomic regions in PRC2-isogenic M3 cells (FDR q ˂ 0.05, fold change ≥2), including promoter (TSS ± 2 kb), distal regulatory (–50 kb from the TSS to the transcriptional end site [TES] + 5 kb), and intergenic (nonpromoter, nondistal regulatory) regions and SEs. (E) Violin plots of mRNA baseline expression of genes associated with PRC2 loss induced significantly increased (SigUP) and decreased (SigDN) H3K27ac at their respective loci in M3 sgCon cells. (F) Correlation of transcriptome and H3K27ac enrichment changes at promoter (TSS ± 2 kb) and nonpromoter (FDR q < 0.05, fold change ≥2) regions. Blue and gray dots represent peaks mapped to genes with (DiffExpGene) and without (nonDiffExpGene) significant transcriptome changes, respectively. (G) HOMER motif analysis of PRC2-loss–associated significantly decreased and increased H3K27ac peaks in PRC2-isogenic M3 cells. e, exponents of 10. (H) ChIP-Seq and ATAC-Seq profiles at the loci of representative IFN-γ–responsive genes, e.g., CCL2, in PRC2-isogenic M3 cells. Pink indicates an H3K27ac change; yellow indicates an H3K27me3 change.