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.
Highlights
Clear cell renal cell carcinoma is a common malignancy
To assess whether transposable element (TE) expression can be pharmacologically modulated in Clear cell renal cell carcinoma (ccRCC) cell lines, we treated a panel of ccRCC cell lines (7860, A498, and UMRC2) and noncancerous transformed kidney cell lines (HKC and renal proximal tubule epithelial [RPTec]) with decitabine, a DNA methylation inhibitor used in the clinic
We showed that decitabine, a DNA hypomethylating agent, could induce endogenous retroviruses (ERVs) expression, and other TEs, such as long interspersed nuclear elements (LINEs)-1, in ccRCC
Summary
Clear cell renal cell carcinoma (ccRCC) is a common malignancy. The development of immune checkpoint blockade (ICB) for the clinical management of ccRCC has achieved remarkable success in subsets of patients [1, 2]. CD8+ T cell infiltration in advanced ccRCC is associated with a poor risk subgroup [6, 7] but with better response to anti-PD1 therapy [1, 8] These associations suggest that modulating tumor immunogenicity to increase T cell infiltration could represent an efficient strategy to promote a set of conditions that allow the tumor immune cells to respond to ICB. While many immune-responsive cancers are characterized by high mutation rates, ccRCCs have modest mutation burden [9] In these regards, we recently reported high expression of endogenous retroviruses (ERVs), a class of transposable element, in a subset of ccRCC tumors, and this can predict response to ICB [10, 11]. 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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