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DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer.


ABSTRACT: Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDA5 IPs showed increased ERV binding with decitabine treatment. Bioinformatic analyses showed the decitabine-induced signature could be associated with increased immune infiltration and response to ICB. Cytokine secretion induced by decitabine could modestly improve T cell activation and robustly enhanced T cell migration. In a small retrospective cohort of metastatic clear cell RCC (ccRCC) patients treated with anti-PD1/PDL1 blockade, activation of some antiviral genes was significantly higher in responders. Thus, we identified a potential strategy to induce TE expression through inhibition of DNA methylation in modulating T cell action via regulation of the innate antiviral pathway.

SUBMITTER: de Cubas AA 

PROVIDER: S-EPMC7308050 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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DNA hypomethylation promotes transposable element expression and activation of immune signaling in renal cell cancer.

de Cubas Aguirre A AA   Dunker William W   Zaninovich Andrew A   Hongo Rachel A RA   Bhatia Anuj A   Panda Anshuman A   Beckermann Kathryn E KE   Bhanot Gyan G   Ganesan Shridar S   Karijolich John J   Rathmell W Kimryn WK  

JCI insight 20200604 11


Recently, we reported that expression of endogenous retroviruses (ERVs) is associated with response to immune checkpoint blockade (ICB) in renal cell carcinoma (RCC). We show that decitabine, a DNA hypomethylating agent, activates transposable element (TE) expression (LINE1 and ERVs ERV3-2 and ERV4700) and antiviral signaling to potentially enhance response to ICB in kidney cancer cell lines and primary cells. KO of RIGI and MDA5 dsRNA sensors attenuated activation of antiviral signaling associa  ...[more]

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