Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Endogenous retroviral signatures predict immunotherapy response in clear cell renal cell carcinoma
Christof C. Smith, … , Sara R. Selitsky, Benjamin G. Vincent
Christof C. Smith, … , Sara R. Selitsky, Benjamin G. Vincent
Published August 23, 2018
Citation Information: J Clin Invest. 2018;128(11):4804-4820. https://doi.org/10.1172/JCI121476.
View: Text | PDF
Research Article Immunology Oncology Article has an altmetric score of 24

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

  • Text
  • PDF
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.

Authors

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

×

Figure 6

hERV 4700 epitope–derived HLA-A*02:01 tetramers identify the presence of gag- and pol-specific T cells in ccRCC.

Options: View larger image (or click on image) Download as PowerPoint
hERV 4700 epitope–derived HLA-A*02:01 tetramers identify the presence of...
(A) Flow cytometric representative gating strategy for identification of CD8+ epitope-specific T cells in ccRCC tumor. (B) Epitope gating for 5 pools of 6 tetramers (top), as well as staining of individual tetramers from pool 4 (bottom) in ccRCC. (C) Percent tetramer-specific CD8+ T cells for epitopes identified in B (tetramer 2: NSWQEMVPV; tetramer 3: MVGPWPRPV) in ccRCC tumors (n = 4) and healthy donor PBMC samples (n = 4). Dots represent values for each sample, with bars representing the mean across each group. Negative controls for gating definitions include tetramer fluorescence-minus-one (FMO) (A) and nonspecific HLA-A*02:01-negative tetramer (B and C). Data presented in Figure 6 represent results from 4 independent experiments.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Blogged by 1
Posted by 22 X users
Referenced in 6 patents
Mentioned in 1 Google+ posts
269 readers on Mendeley
See more details