Faculty, Staff and Student Publications

Publication Date

4-3-2025

Journal

Cell

DOI

10.1016/j.cell.2025.01.046

PMID

40023154

PMCID

PMC11988688

PubMedCentral® Posted Date

4-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated into HLA-bound peptides in ccRCCs, and capable of generating antigen-specific T cell responses. Moreover, ERV expression can be induced in non-ccRCC tumors with clinical-grade HIF stabilizers. These findings have implications for leveraging ERVs for cancer immunotherapy.

Keywords

Humans, Carcinoma, Renal Cell, Endogenous Retroviruses, Kidney Neoplasms, Immunotherapy, Von Hippel-Lindau Tumor Suppressor Protein, Hypoxia-Inducible Factor 1, alpha Subunit, T-Lymphocytes, Basic Helix-Loop-Helix Transcription Factors, ERV, HIF, cancer vaccine, ccRCC, immunopeptidomic, immunotherapy, kidney cancer, neoantigen

Published Open-Access

yes

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