ABSTRACT: Jiang Q, Braun DA, Clauser KR, Ramesh V, Shirole NH, Duke-Cohan JE, Nabilsi N, Karmer NJ, Forman C, Lippincott IE, Klaeger S, Phulphagar KM, Chea V, Kim N, Vanasse AP, Saad E, Parsons T, Carr-Reynolds M, Carulli I, Pinjusic K, Jiang Y, Li R, Syamala S, Rachimi S, Verzani EK, Stevens JD, Lane WJ, Camp SY, Meli K, Pappalardi MB, Herbert ZT, Qiu X, Cejas P, Long HW, Shukla SA, Van Allen EM, Choueiri TK, Churchman LS, Abelin JG, Gurer C, MacBeath G, Childs RW, Carr SA, Keskin DB, Wu CJ, Kaelin WG. 2024.
Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is viewed as an immunogenic tumor 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 allogenic 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 (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.
Steven A. Carr 
