W. Rathmell
Last active: 11/27/2019

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

Panda A, de Cubas AA, Stein M, Riedlinger G, Kra J, Mayer T, Smith CC, Vincent BG, Serody JS, Beckermann KE, Ganesan S, Bhanot G, Rathmell WK
JCI Insight. 2018 3 (16)

PMID: 30135306 · PMCID: PMC6141170 · DOI:10.1172/jci.insight.121522

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 (πERVs) were identified in ccRCC in The Cancer Genome Atlas data set, and tumors were stratified into 3 groups based on their expression levels. πERV-high ccRCC tumors showed increased immune infiltration, checkpoint pathway upregulation, and higher CD8+ T cell fraction in infiltrating leukocytes compared with πERV-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 πERV-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 πERVs is associated with ICA in several solid cancers, including ccRCC, and ERV3-2 expression is associated with response to ICB in ccRCC.

MeSH Terms (19)

Aged Aged, 80 and over Antineoplastic Agents, Immunological B7-H1 Antigen Carcinoma, Renal Cell Datasets as Topic Drug Resistance, Neoplasm Endogenous Retroviruses Female Gene Expression Profiling Gene Expression Regulation, Neoplastic Humans Kidney Neoplasms Male Middle Aged Programmed Cell Death 1 Receptor Progression-Free Survival Retrospective Studies Sequence Analysis, RNA

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