ArticleThe Journal of clinical investigation2022
Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
17 citing papers in PubMed, 22 citations in OpenAlex.
- Immune landscape characterization of neurofibromas with atypical features in Neurofibromatosis1 reveals PD-1 and the Tim-3/Galectin-9 pathway as potential therapeutic targets.Acta neuropathologica communications · 2026Article
- The Cell Surface Proteome of Malignant Peripheral Nerve Sheath Tumors Reveals Therapeutic Targets.bioRxiv : the preprint server for biology · 2026Article
- Single-cell transcriptomic profiling of malignant peripheral nerve sheath tumors.Neuro-oncology advances · 2026Review
- Spatial transcriptomics: Advances and challenges in peripheral nerve sheath tumor.Neuro-oncology · 2025Article
- A Sequencing Overview of Malignant Peripheral Nerve Sheath Tumors: Findings and Implications for Treatment.Cancers · 2025Review
- UBR5 in Tumor Biology: Exploring Mechanisms of Immune Regulation and Possible Therapeutic Implications in MPNST.Cancers · 2025Review
- Unraveling resistance to immune checkpoint inhibitors in HNSCC: from mechanisms to combination therapies.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Multidimensional Immunotyping of Human NF1-Associated Peripheral Nerve Sheath Tumors Uncovers Tumor-Associated Macrophages as Key Drivers of Immune Evasion in the Tumor Microenvironment.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Conditionally replicative adenovirus as a therapy for malignant peripheral nerve sheath tumors.Molecular therapy. Oncology · 2024Article
- STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.The Journal of clinical investigation · 2024Article
- TheCancers · 2024Review
- Clonal Evolution in Healthy and Premalignant Tissues: Implications for Early Cancer Interception Strategies.Cancer prevention research (Philadelphia, Pa.) · 2023Review
- The cancer epigenome: Non-cell autonomous player in tumor immunity.Cancer science · 2023Review
- BAP1 in cancer: epigenetic stability and genome integrity.Discover oncology · 2022Review
- Analysis of treatment sequence and outcomes in patients with relapsed malignant peripheral nerve sheath tumors.Neuro-oncology advancesArticle
- The cell surface proteome of malignant peripheral nerve sheath tumors reveals therapeutic targets.Neuro-oncology advancesArticle
- Multiomic analyses reveal new targets of polycomb repressor complex 2 in Schwann lineage cells and malignant peripheral nerve sheath tumors.Neuro-oncology advancesArticle
Corrections and comments
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Authors and funding
26 authors at 5 institutions in 4 countries.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.