Resumen
How cancer-associated chromatin abnormalities shape tumor-immune interaction remains incompletely understood. Recent studies have linked DNA hypomethylation and de-repression of retrotransposons to anti-tumor immunity through the induction of interferon response. Here, we report that inactivation of the histone H3K36 methyltransferase NSD1, which is frequently found in squamous cell carcinomas (SCCs) and induces DNA hypomethylation, unexpectedly results in diminished tumor immune infiltration. In syngeneic and genetically engineered mouse models of head and neck SCCs, NSD1-deficient tumors exhibit immune exclusion and reduced interferon response despite high retrotransposon expression. Mechanistically, NSD1 loss results in silencing of innate immunity genes, including the type III interferon receptor IFNLR1, through depletion of H3K36 di-methylation (H3K36me2) and gain of H3K27 tri-methylation (H3K27me3). Inhibition of EZH2 restores immune infiltration and impairs the growth of Nsd1-mutant tumors. Thus, our work uncovers a druggable chromatin cross talk that regulates the viral mimicry response and enables immune evasion of DNA hypomethylated tumors.
Idioma original | English |
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Páginas (desde-hasta) | 3901-3918.e7 |
Publicación | Molecular Cell |
Volumen | 82 |
N.º | 20 |
DOI | |
Estado | Published - oct. 20 2022 |
Financiación
We thank members of the Lu lab for critical reading of the manuscript. We thank Chavez lab for the technical support of CRISPRa experiment. This research was supported by US National Institutes of Health (NIH) grants ( P01CA196539 to C.L. and J.M.; R01DK132251 to C.L. and J.Q.; R01DE031873 , R01CA266978 , and R35GM138181 to C.L.; NCI Cancer Center Support Grant P30CA013696 ) and funding from the Concern Foundation (to C.L.). C.L. acknowledges support from the Pew-Stewart Scholars for Cancer Research Award . B.I. acknowledges support from NIH ( R37CA258829 and R21CA263381 ) and Burroughs Wellcome Fund Career Award for Medical Scientists. A.C. acknowledges support from NIH ( R01CA197774 and R01CA227450 ) and the Pershing Square Sohn Cancer Research Award . J.Q. acknowledges support from NIH ( R01CA197774 and R01CA227450 ). Z.Z. acknowledges support from NIH ( R35 GM118015 ). Flow cytometry analysis and cell sorting were performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10OD020056 . Schematic diagrams were created using BioRender. We thank members of the Lu lab for critical reading of the manuscript. We thank Chavez lab for the technical support of CRISPRa experiment. This research was supported by US National Institutes of Health (NIH) grants (P01CA196539 to C.L. and J.M.; R01DK132251 to C.L. and J.Q.; R01DE031873, R01CA266978, and R35GM138181 to C.L.; NCI Cancer Center Support Grant P30CA013696) and funding from the Concern Foundation (to C.L.). C.L. acknowledges support from the Pew-Stewart Scholars for Cancer Research Award. B.I. acknowledges support from NIH (R37CA258829 and R21CA263381) and Burroughs Wellcome Fund Career Award for Medical Scientists. A.C. acknowledges support from NIH (R01CA197774 and R01CA227450) and the Pershing Square Sohn Cancer Research Award. J.Q. acknowledges support from NIH (R01CA197774 and R01CA227450). Z.Z. acknowledges support from NIH (R35 GM118015). Flow cytometry analysis and cell sorting were performed in the CCTI Flow Cytometry Core, supported in part by the Office of the Director, National Institutes of Health under awards S10OD020056. Schematic diagrams were created using BioRender. Y.L. E.M.G. X.C. and C.L. conceived the study. Y.L. E.M.G. and X.C. executed the experimental work with the help of X.X. J.T.M. G.L. D.K. E.D. and T.T. N.F. C.H. Z.L. Z.Z. B.I. J.Q. A.C. J.M. A.J.Y. and L.A. provided reagents, expertise, and feedback. C.L.M. and C.L. supervised the study. Y.L. E.M.G. X.C. and C.L. wrote the manuscript with contributions and input from all of the authors. B.I. is a paid consultant for Volastra Therapeutics.
Financiadores | Número del financiador |
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Volastra Therapeutics | |
National Institutes of Health | R01DE031873, R35GM138181, R01DK132251 |
National Cancer Institute | R01CA266978, R21CA263381, P01CA196539, R01CA197774, P30CA013696, R01CA227450, R37CA258829 |
Office of the Director | S10OD020056 |
Burroughs Wellcome Fund | |
Concern Foundation | |
Pershing Square Sohn Cancer Research Alliance | R35 GM118015 |
ASJC Scopus Subject Areas
- Molecular Biology
- Cell Biology