title: Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas.
abstract: Cancer vaccines have been developed to instruct the endogenous immune responses to autologous tumors and to generate durable clinical responses. However, the therapeutic benefits of cancer vaccines remain insufficient due to the multiple immunosuppressive signals delivered by tumors. Thus, to improve the clinical efficacy of cancer immunotherapy, it is important to develop new modalities to overcome immunosuppressive tumor microenvironments and elicit effective antitumor immune responses. In this study, we show that novel monoclonal antibodies (mAbs) specifically targeting either T cell immunoglobulin mucin protein-3 (TIM-3) or T cell immunoglobulin mucin protein-4 (TIM-4) enhance the therapeutic effects of vaccination against established B16 murine melanomas. This is true for vaccination with irradiated B16 melanoma cells engineered to express the flt3 ligand gene (FVAX). More importantly, combining anti-TIM-3 and anti-TIM-4 mAbs markedly increased vaccine-induced antitumor responses against established B16 melanoma. TIM-3 blockade mainly stimulated antitumor effector activities via natural killer cell-dependent mechanisms, while CD8(+) T cells served as the main effectors induced by anti-TIM-4 mAb. Our findings reveal that therapeutic manipulation of TIM-3 and TIM-4 may provide a novel strategy for improving the clinical efficacy of cancer immunotherapy.
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido, 060-0815, Japan.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Baghdadi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nagao
authors.forename: Hironori
authors.initials: H
authors.lastname: Yoshiyama
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D007694:Killer Cells, Natural / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D011991:Receptors, Virus / Q000037:antagonists & inhibitors* / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D019496:Cancer Vaccines; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D011991:Receptors, Virus; C500399:TIM-4 protein, mouse