Journal
JCI INSIGHT
Volume 5, Issue 11, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.137569
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Categories
Funding
- Vanderbilt Ingram Cancer Center
- K01 NCI Mentored Research Scientist Development Award [1K01CA245231-01]
- American Cancer Society Postdoctoral Fellowship Award [132921-PF-18-183-01-TBG]
- Pew Charitable Trusts as a Pew Biomedical Scholar
- ORIEN grant [826489]
- Department of Defense KRCP grant [KC180159]
- New Jersey Comission on Cancer Research (NJCCR)
- NCI [R01CA2435478, R01CA20275200]
- Department of Defense [KC180159]
- BCRF
- Hugs for Brady
- AHEPA Foundation
- Jartrude Fogarty Trust
- [R01CA198482]
- [T32CA009582-28]
- [K12CA090625]
- [R01AI141448]
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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 MDAS dsRNA sensors attenuated activation of antiviral signaling associated with DNA hypomethylation, and RIGI and MDAS dsRNA 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.
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