HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy
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.
Authors
- Derin B. Keskin (ORCID: https://orcid.org/0000-0002-8496-6181)
- Paloma Cejas (ORCID: https://orcid.org/0000-0002-2090-7748)
- Karl R. Clauser (ORCID: https://orcid.org/0000-0002-1052-9456)
- Eddy Saad (ORCID: https://orcid.org/0000-0001-8700-9312)
- Teagan Parsons
- Suzanna Rachimi (ORCID: https://orcid.org/0000-0001-7294-8683)
- Nicholas J. Kramer (ORCID: https://orcid.org/0000-0003-4557-8343)
- Jennifer G. Abelin (ORCID: https://orcid.org/0000-0001-5262-7241)
- Melissa Carr-Reynolds
- Nancy Nabilsi
- Vipheaviny Chea (ORCID: https://orcid.org/0000-0002-6592-8710)
- Isabel Carulli (ORCID: https://orcid.org/0000-0001-8136-4719)
- William J. Lane (ORCID: https://orcid.org/0000-0002-1097-5229)
- Susan Klaeger (ORCID: https://orcid.org/0000-0002-0074-5163)
- Yijia Jiang (ORCID: https://orcid.org/0000-0002-0239-6999)
- Steven A. Carr (ORCID: https://orcid.org/0000-0002-7203-4299)
- Eliezer M. Van Allen (ORCID: https://orcid.org/0000-0002-0201-4444)
- Xintao Qiu (ORCID: https://orcid.org/0000-0002-8560-7017)
- Jonathan S. Duke‐Cohan (ORCID: https://orcid.org/0000-0002-9478-9609)
- Gavin MacBeath (ORCID: https://orcid.org/0000-0003-2585-6772)
- Catherine J. Wu (ORCID: https://orcid.org/0000-0002-3348-5054)
- Nawoo Kim
- Toni K. Choueiri (ORCID: https://orcid.org/0000-0002-9201-3217)
- Sudeepa Syamala (ORCID: https://orcid.org/0000-0003-0476-3083)
- Eva K. Verzani (ORCID: https://orcid.org/0009-0004-0846-4878)
- Kshiti Meera Phulphagar
- Melissa B. Pappalardi (ORCID: https://orcid.org/0000-0001-8457-1625)
- Nitin H. Shirole (ORCID: https://orcid.org/0000-0002-2579-456X)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Katarina Pinjušić (ORCID: https://orcid.org/0000-0002-5070-3340)
- Jonathan Stevens
- David A. Braun (ORCID: https://orcid.org/0000-0003-4543-5553)
- Cagan Gurer
- L. Stirling Churchman (ORCID: https://orcid.org/0000-0003-3888-2574)
- Vijyendra Ramesh (ORCID: https://orcid.org/0000-0001-8818-6863)
- Zachary T. Herbert (ORCID: https://orcid.org/0000-0001-9401-2464)
- Sachet A. Shukla (ORCID: https://orcid.org/0000-0003-2445-3584)
- Qinqin Jiang (ORCID: https://orcid.org/0000-0003-0874-1797)
- Sabrina Y. Camp (ORCID: https://orcid.org/0000-0002-9695-5527)
- William G. Kaelin (ORCID: https://orcid.org/0000-0002-0574-4856)
- Kevin Meli (ORCID: https://orcid.org/0000-0002-9579-3829)
- Rong Li (ORCID: https://orcid.org/0000-0001-7266-0241)
- Isabelle E Lippincott
- Cleo Forman
- Richard Childs
- Allison P. Vanasse
Institutions
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- National Institutes of Health (US)
- The University of Texas MD Anderson Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Yale Cancer Center (US)
- National Heart, Lung, and Blood Institute (US)
- Boston VA Research Institute (US)
- Dana-Farber Cancer Institute (US)
- TScan Therapeutics (United States) (US)
- Harvard Stem Cell Institute (US)
- Dana-Farber Brigham Cancer Center (US)
- Massachusetts Institute of Technology (US)
- Epigenomics (Germany) (DE)
Publication Details
- Journal
- Cell
- Published
- 2025-02-28
- DOI
- https://doi.org/10.1016/j.cell.2025.01.046
- Citations
- 43
- Primary Topic
- Cancer Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 53.01
Funders
- U.S. Department of Defense
- Howard Hughes Medical Institute
- National Cancer Institute