Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses
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 under...
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2022-09-01
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| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI153437 |
| _version_ | 1827768256809664512 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Juan Yan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:09:42Z |
| format | Article |
| id | doaj.art-5f861c04fcd24ec597718aa39450c410 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:42Z |
| publishDate | 2022-09-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-5f861c04fcd24ec597718aa39450c4102023-11-07T16:19:17ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382022-09-0113217Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic virusesJuan YanYuedan ChenAmish J. PatelSarah WardaCindy J. LeeBriana G. NixonElissa W.P. WongMiguel A. Miranda-RománNing YangYi WangMohini R. PachaiJessica SherEmily GiffFanying TangEkta KhuranaSam SingerYang LiuPhillip M. Galbo Jr.Jesper L.V. MaagRichard P. KocheDeyou ZhengCristina R. AntonescuLiang DengMing O. LiYu ChenPing ChiImmune 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.https://doi.org/10.1172/JCI153437OncologyTherapeutics |
| spellingShingle | 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 Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses The Journal of Clinical Investigation Oncology Therapeutics |
| title | Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses |
| title_full | Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses |
| title_fullStr | Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses |
| title_full_unstemmed | Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses |
| title_short | Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert microenvironment and is sensitized by immunogenic viruses |
| title_sort | tumor intrinsic prc2 inactivation drives a context dependent immune desert microenvironment and is sensitized by immunogenic viruses |
| topic | Oncology Therapeutics |
| url | https://doi.org/10.1172/JCI153437 |
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