Rxivist logo

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment and confers resistance to immunotherapy

By Juan Yan, Yuedan Chen, Amish J. Patel, Sarah Warda, Briana G. Nixon, Elissa W. P. Wong, Miguel A. Miranda-Roman, Cindy J. Lee, Ning Yang, Yi Wang, Jessica Sher, Emily Giff, Fanying Tang, Ekta Khurana, Sam Singer, Yang Liu, Phillip M. Galbo, Jesper L. Maag, Richard Koche, Deyou Zheng, Liang Deng, Cristina R. Antonescu, Ming Li, Yu Chen, Ping Chi

Posted 27 May 2022
bioRxiv DOI: 10.1101/2022.05.27.493507

Immune checkpoint blockade (ICB) has demonstrated clinical success in inflamed tumors with significant 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 demonstrate that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST) and sporadically in other cancer types, drives a context-dependent immune-desert TME. PRC2 inactivation reprograms the chromatin landscape that leads to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., interferon gamma) to PRC2-regulated development and cellular differentiation transcriptional programs. Further, PRC2 inactivation reprograms the TME, leads to diminished tumor immune infiltrates and immune evasion through reduced chemokine production and impaired antigen presentation and T-cell priming, and confers ICB primary resistance through blunted T-cell recruitment in vivo. We demonstrate that strategies that enhancing innate immunity via intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) leads to increased tumor immune infiltrates and sensitizes PRC2-loss tumors to ICB. Our results provide novel molecular mechanisms of context-dependent dysfunctional epigenetic reprogramming that underline the immune-desert phenotype in MPNST and other cancers with PRC2 inactivation. Importantly, our findings highlight genetic-inactivation of PRC2 as a novel context-dependent ICB therapeutic resistance biomarker in cancer, and caution that therapeutic strategies that non-selectively target PRC2 in the host may lead to undesirable context-dependent immune evasion and ICB resistance in tumors. Our studies also point to intratumoral delivery of immunogenic therapeutic viruses as an initial strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

Download data

  • Downloaded 224 times
  • Download rankings, all-time:
    • Site-wide: 176,021
    • In cancer biology: 5,444
  • Year to date:
    • Site-wide: 38,440
  • Since beginning of last month:
    • Site-wide: 61,601

Altmetric data


Downloads over time

Distribution of downloads per paper, site-wide


PanLingua

News