Endogenous retrovirus expression is associated with response to immune checkpoint blockade in clear cell renal cell carcinoma
Open accessAbstract
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.
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Increased expression of ERVs, including a full-length HERV4700 element, was significantly associated with improved response to PD-1/PD-L1 blockade in clear cell renal cell carcinoma.
“increased expression of ERVs, including a full-length HERV4700 element, was significantly associated with improved response to PD-1/PD-L1 blockade in clear cell renal cell carcinoma32,33.”
From Multi-omic analysis of hepatocellular carcinoma reveals aberrant cis-regulatory changes and dysregulated retrotransposons with prognostic potential (2025) · cites this paper as [33]
The Introduction and Figure 3 caption (page not available in our copy) report that higher ERV3-2 expression was significantly associated with response to PD-1/PD-L1 blockade in clear cell renal cell carcinoma. The cited paper does not identify ERV3-2 as a full-length HERV4700 element or report a response association for HERV4700; a search for HERV4700 found no passage addressing it. (LLM, conf=0.88)
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- Authors
- Panda, A., de Cubas, A. A., Stein, M., Riedlinger, G., Kra, J., Mayer, T., Smith, C. C., Vincent, B. G., Serody, J. S., Beckermann, K. E., Ganesan, S., Bhanot, G., & Rathmell, W. K.
- Affiliations
- Rutgers, The State University of New Jersey (US)
- Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
- Rutgers Cancer Institute (US)
- University of North Carolina at Chapel Hill (US)
- Vanderbilt University (US)
- Corresponding author
- Ganesan, Shridar
- Bhanot, Gyan
- Rathmell, W. Kimryn
- ORCID
- Venue
- JCI Insight
- Published
- 2018-08-23
- Volume
- 3
- Issue
- 16
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6141170
- OpenAlex
- W2888758049
- Cited by
- 181
- References
- 32
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 16 · 2023: 20 · 2022: 31 · 2021: 35 · 2020: 28 · 2019: 14
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- Funders
- NIH (NIH: R01-CA198482 (WKR),K24-CA172355 (WKR),T32-CA009582-28 (AAD),P30-CA072720 (AP)
- U.S. Department of Defense (DOD-CA160728P1)
- Cancer Research Institute (Irvington Fellowship)
- National Science Foundation (PHY-1607611)
- Val Skinner Foundation (NA)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal cell carcinoma treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- endogenous retroviruses, clear cell renal cell carcinoma, immune checkpoint blockade, tumor immune infiltration, CD8+ T cells, PD-1/PD-L1 blockade, treatment response prediction, BAP1 mutation, histone methylation, chromatin regulation, HER2-negative breast cancer, colon cancer, head and neck squamous cell carcinoma
- MeSH terms
- Antineoplastic Agents, Immunological, Progression-Free Survival, Aged, Aged, 80 and over, Carcinoma, Renal Cell, Female, Humans, Kidney Neoplasms, Male, Middle Aged, Retrospective Studies, Gene Expression Regulation, Neoplastic, Sequence Analysis, RNA, Drug Resistance, Neoplasm, Endogenous Retroviruses, Gene Expression Profiling, B7-H1 Antigen, Programmed Cell Death 1 Receptor, Datasets as Topic
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