Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses Journal Article
| Authors: | Yan, J.; Chen, Y.; Patel, A. J.; Warda, S.; Lee, C. J.; Nixon, B. G.; Wong, E. W. P.; Miranda-Román, M. A.; Yang, N.; Wang, Y.; Pachai, M. R.; Sher, J.; Giff, E.; Tang, F.; Khurana, E.; Singer, S.; Liu, Y.; Galbo, P. M. Jr; Maag, J. L. V.; Koche, R. P.; Zheng, D.; Antonescu, C. R.; Deng, L.; Li, M. O.; Chen, Y.; Chi, P. |
| Article 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. © 2022, Yan et al. |
| Keywords: | genetics; neoplasm; neoplasms; chromatin; virus; tumor microenvironment; viruses; polycomb repressive complex 2; humans; human |
| Journal Title: | Journal of Clinical Investigation |
| Volume: | 132 |
| Issue: | 17 |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Date Published: | 2022-09-01 |
| Start Page: | e153437 |
| Language: | English |
| DOI: | 10.1172/jci153437 |
| PUBMED: | 35852856 |
| PROVIDER: | scopus |
| PMCID: | PMC9433107 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 October 2022 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
MSK Authors
Related MSK Work