Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma

Although a subset of clear cell renal cell carcinoma (ccRCC) patients respond to immune checkpoint blockade (ICB), predictors of response remain uncertain. We investigated whether abnormal expression of endogenous retroviruses (ERVs) in tumors is associated with local immune checkpoint activation (ICA) and response to ICB. Twenty potentially immunogenic ERVs (pi ERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. pi ERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8(+) T cell fraction in infiltrating leukocytes compared with pi ERV-low ccRCC tumors. Similar results were observed in ER+/HER2(-) breast, colon, and head and neck squamous cell cancers. ERV expression correlated with expression of genes associated with histone methylation and chromatin regulation, and pi ERV-high ccRCC was enriched in BAP1 mutant tumors. ERV3-2 expression correlated with ICA in 11 solid cancers, including the 4 named above. In a small retrospective cohort of 24 metastatic ccRCC patients treated with single-agent PD-1/PD-L1 blockade, ERV3-2 expression in tumors was significantly higher in responders compared with nonresponders. Thus, abnormal expression of pi ERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.