| Abstract: |
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 (Tyrpl)- WM, derived from Tyrpl 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 Tyrpl-WM, but not native Tyrpl, induced specific CD8<sup>+</sup> and CD4 <sup>+</sup> T-cell responses against denned mutated epitopes in tumor-draining lymph nodes and in tumors. Subsequently, specific CD8<sup>+</sup> T-cell responses contracted as a minority of tumors progressed. B16 melanomas expressing Tyrpl-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<sup>+</sup> T cells recognizing a peptide derived from the Tyrpl-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<sup>+</sup> T-cell responses to specific mutations and to lead to tumor rejection. © 2009 American Association tor Cancer Research. dio: 10.1158/0008-5472.CAN-08-2779. |
| Keywords: |
controlled study; gene mutation; nonhuman; cd8+ t lymphocyte; t-lymphocytes; animal cell; mouse; animals; mice; gene expression; animal experiment; animal model; in vivo study; mice, scid; transfection; mice, inbred c57bl; cellular immunity; amino acid sequence; molecular sequence data; fibrosarcoma; membrane glycoproteins; disease progression; immunogenicity; lymph node; cd4+ t lymphocyte; epitope; melanoma b16; melanoma, experimental; autoantigens; tumor immunity; immunomodulation; tumor growth; mice, inbred nod; okt 4; glucocorticoid induced tumor necrosis factor receptor; okt 8; tyrosinase related protein 1; lymphatic drainage; tumor rejection; epitopes, t-lymphocyte; oxidoreductases
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