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 4

PRC2 loss dampens the IFN-γ response in tumor cells through decreased chromatin accessibility.

Options: View larger image (or click on image) Download as PowerPoint
PRC2 loss dampens the IFN-γ response in tumor cells through decreased ch...
(A) PCA of chromatin accessibility by ATAC-Seq in PRC2-wt (sgCon) and PRC2-loss (sgSUZ12) human MPNST cells with or without IFN-γ stimulation. (B) K-means clustering analysis of the chromatin accessibility changes in PRC2-isogenic M3 cells with or without IFN-γ stimulation. Cells were treated with or without 10 ng/mL IFN-γ for 24 hours followed by ATAC-Seq. Enriched IRF motifs by HOMER de novo motif analysis in clusters 2, 6, and 7. (C and D) Comparison of significantly enriched pathways between cluster 7 (C) and cluster 2 (D) by GO analysis. (E and F) IFN-γ dose–dependent mRNA expression changes of IFN-γ–responsive genes by qRT-PCR without (E) or with (F) PRC2-loss–associated chromatin accessibility changes (n = 3). Results were normalized to sgCon without the stimulation condition. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by multiple unpaired t tests (E and F). (P < 0.05, FDR q < 0.05 and a fold change ≥2 was significant). Data indicate the mean ± SEM.