HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy

Qinqin Jiang; David A Braun; Karl R Clauser; Vijyendra Ramesh; Nitin H Shirole; Joseph E Duke-Cohan; Nancy Nabilsi; Nicholas J Kramer; Cleo Forman; Isabelle E Lippincott; Susan Klaeger; Kshiti M Phulphagar; Vipheaviny Chea; Nawoo Kim; Allison P Vanasse; Eddy Saad; Teagan Parsons; Melissa Carr-Reynolds; Isabel Carulli; Katarina Pinjusic; Yijia Jiang; Rong Li; Sudeepa Syamala; Suzanna Rachimi; Eva K Verzani; Jonathan D Stevens; William J Lane; Sabrina Y Camp; Kevin Meli; Melissa B Pappalardi; Zachary T Herbert; Xintao Qiu; Paloma Cejas; Henry W Long; Sachet A Shukla; Eliezer M Van Allen; Toni K Choueiri; L Stirling Churchman; Jennifer G Abelin; Cagan Gurer; Gavin MacBeath; Richard W Childs; Steven A Carr; Derin B Keskin; Catherine J Wu; William G Kaelin Jr

doi:10.1016/j.cell.2025.01.046

HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy

Cell. 2025 Apr 3;188(7):1807-1827.e34. doi: 10.1016/j.cell.2025.01.046. Epub 2025 Feb 28.

Authors

Qinqin Jiang¹, David A Braun², Karl R Clauser³, Vijyendra Ramesh¹, Nitin H Shirole¹, Joseph E Duke-Cohan⁴, Nancy Nabilsi⁵, Nicholas J Kramer⁶, Cleo Forman⁷, Isabelle E Lippincott³, Susan Klaeger³, Kshiti M Phulphagar³, Vipheaviny Chea⁴, Nawoo Kim⁴, Allison P Vanasse⁴, Eddy Saad⁸, Teagan Parsons⁵, Melissa Carr-Reynolds⁵, Isabel Carulli⁴, Katarina Pinjusic⁹, Yijia Jiang¹⁰, Rong Li¹⁰, Sudeepa Syamala¹⁰, Suzanna Rachimi³, Eva K Verzani³, Jonathan D Stevens¹¹, William J Lane¹¹, Sabrina Y Camp⁷, Kevin Meli¹, Melissa B Pappalardi¹², Zachary T Herbert¹³, Xintao Qiu¹⁰, Paloma Cejas¹⁰, Henry W Long¹⁰, Sachet A Shukla¹⁴, Eliezer M Van Allen⁷, Toni K Choueiri¹⁵, L Stirling Churchman⁶, Jennifer G Abelin³, Cagan Gurer⁵, Gavin MacBeath⁵, Richard W Childs¹⁶, Steven A Carr¹⁷, Derin B Keskin¹⁸, Catherine J Wu¹⁹, William G Kaelin Jr²⁰

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
² Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, USA.
³ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁴ Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
⁵ TScan Therapeutics, Waltham, MA 02451, USA.
⁶ Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA.
⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁰ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹¹ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹² Cancer Epigenetics Research Unit, Oncology, GSK, Collegeville, PA 19426, USA.
¹³ Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
¹⁴ Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁵ Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA.
¹⁶ Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
¹⁷ Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: scarr@broad.mit.edu.
¹⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Translational Immunogenomics Laboratory, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Computer Science, Metropolitan College, Boston University, Boston, MA 02215, USA; Section for Bioinformatics, Department of Health Technology, Technical University of Denmark 2800 Lyngby, Denmark. Electronic address: derin_keskin@dfci.harvard.edu.
¹⁹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA. Electronic address: catherine_wu@dfci.harvard.edu.
²⁰ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

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: ERV; HIF; cancer vaccine; ccRCC; immunopeptidomic; immunotherapy; kidney cancer; neoantigen.

MeSH terms

Basic Helix-Loop-Helix Transcription Factors* / metabolism
Carcinoma, Renal Cell* / genetics
Carcinoma, Renal Cell* / immunology
Carcinoma, Renal Cell* / metabolism
Carcinoma, Renal Cell* / therapy
Carcinoma, Renal Cell* / virology
Endogenous Retroviruses* / genetics
Endogenous Retroviruses* / metabolism
Humans
Hypoxia-Inducible Factor 1, alpha Subunit* / metabolism
Immunotherapy
Kidney Neoplasms* / immunology
Kidney Neoplasms* / metabolism
Kidney Neoplasms* / therapy
Kidney Neoplasms* / virology
T-Lymphocytes / immunology
Von Hippel-Lindau Tumor Suppressor Protein / metabolism

Substances

Von Hippel-Lindau Tumor Suppressor Protein
Hypoxia-Inducible Factor 1, alpha Subunit
Basic Helix-Loop-Helix Transcription Factors
VHL protein, human

Abstract

MeSH terms

Substances

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