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.
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Acknowledgments
We thank Professor James P. Allison and Dr. Michael A. Curran (Memorial Sloan-Kettering Cancer Center) for the B16-Flt3L cell line, Dr. Heiichiro Udono (Okayama University) for the B16-OVA cell line, Dr. Jedd Wolchok (Memorial Sloan-Kettering Cancer Center) for DNA plasmids and Dr. Shigeo Koyasu (Keio University) for the OT-I mice. In addition, we wish to extend appreciation to Mr. Tsunaki Yamashina for assistance with animal care. This study is partially supported by a Grant-in-Aid for Scientific Research and Scientific Research for Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Takeda Science Foundation, the Sumitomo Foundation and Terumo Life Science Foundation (M. J.); Grant-in-Aid from MEXT and the National Cancer Center Research and Development Fund (H.Ya.).
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The authors declare that they have no conflict of interest.
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Baghdadi, M., Nagao, H., Yoshiyama, H. et al. Combined blockade of TIM-3 and TIM-4 augments cancer vaccine efficacy against established melanomas. Cancer Immunol Immunother 62, 629–637 (2013). https://doi.org/10.1007/s00262-012-1371-9
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DOI: https://doi.org/10.1007/s00262-012-1371-9