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Immune Rejection of Mouse Tumors Expressing Mutated Self

¹ Memorial Sloan-Kettering Cancer Center; ² Weill Medical College and ³ Graduate School of Medical Sciences of Cornell University, New York, New York; and ⁴ Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Requests for reprints: Alan N. Houghton, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room Z-1460, New York, NY 10065. Phone: 646-888-2315; E-mail: a-houghton{at}ski.mskcc.org.

Key Words: mutation • melanoma • differentiation antigen • cancer • immunity

How the immune system recognizes and responds to mutations expressed by cancer cells is a critical issue for cancer immunology. Mutated self-polypeptides are particularly strong tumor-specific rejection antigens for natural tumor immunity, but we know remarkably little about T-cell responses to mutated self during tumor growth in vivo, including levels of response, kinetics, and correlates that predict tumor rejection. To address these questions, a mutated self-antigen, designated tyrosinase-related protein 1 (Tyrp1)-WM, derived from Tyrp1 was expressed in the poorly immunogenic, spontaneously arising B16 melanoma and the immunogenic, chemically induced LiHa fibrosarcoma. Syngeneic mice challenged with LiHa fibrosarcoma cells expressing Tyrp1-WM, but not native Tyrp1, induced specific CD8⁺ and CD4⁺ T-cell responses against defined mutated epitopes in tumor-draining lymph nodes and in tumors. Subsequently, specific CD8⁺ T-cell responses contracted as a minority of tumors progressed. B16 melanomas expressing Tyrp1-WM induced minimal T-cell responses, and no tumor immunity was detected. Treatment with an agonist monoclonal antibody against glucocorticoid-induced tumor necrosis factor receptor family–related gene (GITR) increased the level of CD8⁺ T cells recognizing a peptide derived from the Tyrp1-WM sequence and the proportion of mice rejecting tumors. These results show that B16 tumors expressing mutations that generate strongly immunogenic epitopes naturally induce T-cell responses, which are insufficient to reject tumors. Immune modulation, such as inducing GITR signaling, is required to enhance CD8⁺ T-cell responses to specific mutations and to lead to tumor rejection. [Cancer Res 2009;69(8):3545–53]