TY - JOUR
T1 - Immune rejection of mouse tumors expressing Mutated self
AU - Duan, Fei
AU - Lin, Yun
AU - Liu, Cailian
AU - Engelhorn, Manuel E.
AU - Cohen, Adam D.
AU - Curran, Michael
AU - Sakaguchi, Shimon
AU - Merghoub, Taha
AU - Terzulli, Stephanie
AU - Wolchok, Jedd D.
AU - Houghton, Alan N.
PY - 2009/4/15
Y1 - 2009/4/15
N2 - 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 + and CD4 + T-cell responses against denned 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 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 + 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 + T-cell responses to specific mutations and to lead to tumor rejection.
AB - 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 + and CD4 + T-cell responses against denned 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 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 + 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 + T-cell responses to specific mutations and to lead to tumor rejection.
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U2 - 10.1158/0008-5472.CAN-08-2779
DO - 10.1158/0008-5472.CAN-08-2779
M3 - Article
C2 - 19351857
AN - SCOPUS:65949094161
SN - 0008-5472
VL - 69
SP - 3545
EP - 3553
JO - Cancer Research
JF - Cancer Research
IS - 8
ER -