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.
Cell. 2025 Feb 25 [Epub ahead of print]
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
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; Yale Center of Cellular and Molecular Oncology, Yale School of Medicine, New Haven, CT 06511, 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., TScan Therapeutics, Waltham, MA 02451, USA., Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA 02215, USA., 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 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., 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., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Pathology, Brigham and Women's Hospital, Boston, MA 02215, USA., Cancer Epigenetics Research Unit, Oncology, GSK, Collegeville, PA 19426, USA., Molecular Biology Core Facilities, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA., 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., Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA., Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA. Electronic address: ., 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: ., 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: ., 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: .