Expression of endogenous retroviruses and response to immune checkpoint therapy in renal cell cancer.

Abstract

104 Background: In certain cancers, including renal cell carcinoma (RCC), no clear correlation exists between mutation burden and response to immune checkpoint therapy. To look for other markers of immune activation, we investigated the correlation between expression of endogenous retroviruses (ERV) and evidence of immune checkpoint activation in multiple cancer types. Methods: RNA-seq data of 4,910 tumors of 21 cancers from TCGA was analyzed to identify cancers in which there was correlation between ERV expression and evidence of immune checkpoint activation as shown by increased expression of immune checkpoint genes and evidence of CD8+ T-cell infiltration. Expression of candidate ERVs was measured by quantitative RT-PCR in a set of 20 RCC specimens. Results: In the TCGA clear-cell renal cancer, ER+HER2- breast cancer, and colon cancer datasets showed correlation between expression of a subset of ERVs and markers of local immune checkpoint activation. Using hierarchical clustering, tumors could be classified into 3 groups (high/intermediate/low) based on expression of these ERVs. In all these cancer types, the high ERV expressing group showed evidence of immune activation (robust immune infiltration with high CD8+ T cell fraction) and checkpoint (PD-1, CTLA-4) pathway over-expression. Expression of gene pathways associated with histone modification was significantly correlated with overall ERV expression, suggesting underlying dysregulation of chromatin silencing. Of ERVs analyzed ERV3.2 and ERVK-2 were most consistently associated with markers of immune checkpoint activation in multiple cancer types. For validation, expression of ERVs were measured in tumor sepcimens 20 clear cell renal cancer patients treated with immune checkpoint blockade. Expression of ERV3-2 and ERVK-2, was significantly increased in patients with clinical response to immune checkpoint therapy in this cohort. Conclusions: These data suggest that expression of ERV may be associated with activation of immune checkpoint pathways in renal cell cancer and may predict response to immune checkpoint therapy. Similar associations may also exist in some other solid tumors.