Immune rejection of mouse tumors expressing mutated self.
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.
Duan
Fei
F
Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.
Lin
Yun
Y
Liu
Cailian
C
Engelhorn
Manuel E
ME
Cohen
Adam D
AD
Curran
Michael
M
Sakaguchi
Shimon
S
Merghoub
Taha
T
Terzulli
Stephanie
S
Wolchok
Jedd D
JD
Houghton
Alan N
AN
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000276:immunology; D018450:Disease Progression; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005354:Fibrosarcoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014162:Transfection
D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; D010088:Oxidoreductases; C079621:Tyrp1 protein, mouse