Cited by 304Cancer Immunotherapy and BiomarkersRenal cell carcinoma treatmentImmunotherapy and Immune Responses

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Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma

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Smith, Christof C., Beckermann, Kathryn E., Bortone, Dante S., De Cubas, Aguirre A., Bixby, Lisa M., Lee, Samuel J., Panda, Anshuman, Ganesan, Shridar, Bhanot, Gyan, Wallen, Eric M., Milowsky, Matthew I., Kim, William Y., Rathmell, W. Kimryn, Swanstrom, Ronald, Parker, Joel S., Serody, Jonathan S., Selitsky, Sara R., Vincent, Benjamin G.·2018·Journal of Clinical Investigation

DOI 10.1172/jci121476PMC PMC6205406

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Abstract

Human endogenous retroviruses (hERVs) are remnants of exogenous retroviruses that have integrated into the genome throughout evolution. We developed a computational workflow, hervQuant, which identified more than 3,000 transcriptionally active hERVs within The Cancer Genome Atlas (TCGA) pan-cancer RNA-Seq database. hERV expression was associated with clinical prognosis in several tumor types, most significantly clear cell renal cell carcinoma (ccRCC). We explored two mechanisms by which hERV expression may influence the tumor immune microenvironment in ccRCC: (i) RIG-I-like signaling and (ii) retroviral antigen activation of adaptive immunity. We demonstrated the ability of hERV signatures associated with these immune mechanisms to predict patient survival in ccRCC, independent of clinical staging and molecular subtyping. We identified potential tumor-specific hERV epitopes with evidence of translational activity through the use of a ccRCC ribosome profiling (Ribo-Seq) dataset, validated their ability to bind HLA in vitro, and identified the presence of MHC tetramer-positive T cells against predicted epitopes. hERV sequences identified through this screening approach were significantly more highly expressed in ccRCC tumors responsive to treatment with programmed death receptor 1 (PD-1) inhibition. hervQuant provides insights into the role of hERVs within the tumor immune microenvironment, as well as evidence that hERV expression could serve as a biomarker for patient prognosis and response to immunotherapy.

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Additional file 2 of Spatiotemporal evolution of the clear cell renal cell carcinoma microenvironment links intra-tumoral heterogeneity to immune escape
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Additional file 3 of Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
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Additional file 5 of Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
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Additional file 4 of Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
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Additional file 2 of Development and validation of a VHL-associated immune prognostic signature for clear cell renal cell carcinoma
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Authors: Smith, C. C., Beckermann, K. E., Bortone, D. S., De Cubas, A. A., Bixby, L. M., Lee, S. J., Panda, A., Ganesan, S., Bhanot, G., Wallen, E. M., Milowsky, M. I., Kim, W. Y., Rathmell, W. K., Swanstrom, R., Parker, J. S., Serody, J. S., Selitsky, S. R., & Vincent, B. G.
Affiliations: University of North Carolina at Chapel Hill (US)
Vanderbilt University Medical Center (US)
Rutgers, The State University of New Jersey (US)
ORCID: Smith, Christof C.
Beckermann, Kathryn E.
Bortone, Dante S.
De Cubas, Aguirre A.
Bixby, Lisa M.
Lee, Samuel J.
Panda, Anshuman
Ganesan, Shridar
Bhanot, Gyan
Milowsky, Matthew I.
Kim, William Y.
Rathmell, W. Kimryn
Swanstrom, Ronald
Parker, Joel S.
Serody, Jonathan S.
Selitsky, Sara R.
Vincent, Benjamin G.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2018-10-02
Volume: 128
Issue: 11
Pages: 4804-4820
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci121476
PMC: PMC6205406
OpenAlex: W2888593931
Cited by: 303
References: 63
Citations by year: 2026: 16 · 2025: 37 · 2024: 30 · 2023: 48 · 2022: 52 · 2021: 47 · 2020: 53 · 2019: 18 · 2018: 2
FWCI: 11.28
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
Locations: Journal of Clinical Investigation (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Rutgers University Community Repository (Rutgers University) (submittedVersion)
Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
UNC Libraries
Funders: UNC Oncology Clinical Translational Research Training Program (5K12CA120780)
National Institute of Health (5-P50-CA058223-22, 2-P30-CA016086-40, 1-U24-CA210988-01, U54-CA198999, 1F30CA225136-01)
Forbeck Foundation Collaborative Research Award (NA)
UNC University Cancer Research Fund (NA)
Merck-Cancer Research Institute Irvington Postdoctoral Fellowship (NA)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Health Sciences › Medicine › Oncology › Renal cell carcinoma treatment
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: human endogenous retroviruses, clear cell renal cell carcinoma, immunotherapy response prediction, anti-PD-1 therapy, tumor immune microenvironment, HLA binding, prognostic factors, ribosome profiling, T cell response
MeSH terms: Carcinoma, Renal Cell, Humans, Immunotherapy, Kidney Neoplasms, Prognosis, Endogenous Retroviruses, Tumor Microenvironment

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Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma

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