Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4

Journal of Experimental Medicine - Tập 210 Số 7 - Trang 1389-1402 - 2013
Rikke Holmgaard1,2, Dmitriy Zamarin3,1,2, David H. Munn4, Jedd D. Wolchok3,5,2,6, James P. Allison1,7
1Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 1
2Swim Across America Laboratory/Ludwig Collaborative Research Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065 2
3Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065 3
4Cancer Center and Department of Pediatrics, Georgia Regents University, Augusta, GA 30912 4
5Ludwig Institute for Cancer Research, New York, NY 10065 6
6Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10065 5
7The University of Texas, MD Anderson Cancer Center, Department of Immunology, Houston, TX 77030 7

Tóm tắt

The cytotoxic T lymphocyte antigen-4 (CTLA-4)–blocking antibody ipilimumab results in durable responses in metastatic melanoma, though therapeutic benefit has been limited to a fraction of patients. This calls for identification of resistance mechanisms and development of combinatorial strategies. Here, we examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the antitumor efficacy of CTLA-4 blockade. In IDO knockout mice treated with anti–CTLA-4 antibody, we demonstrate a striking delay in B16 melanoma tumor growth and increased overall survival when compared with wild-type mice. This was also observed with antibodies targeting PD-1–PD-L1 and GITR. To highlight the therapeutic relevance of these findings, we show that CTLA-4 blockade strongly synergizes with IDO inhibitors to mediate rejection of both IDO-expressing and nonexpressing poorly immunogenic tumors, emphasizing the importance of the inhibitory role of both tumor- and host-derived IDO. This effect was T cell dependent, leading to enhanced infiltration of tumor-specific effector T cells and a marked increase in the effector-to-regulatory T cell ratios in the tumors. Overall, these data demonstrate the immunosuppressive role of IDO in the context of immunotherapies targeting immune checkpoints and provide a strong incentive to clinically explore combination therapies using IDO inhibitors irrespective of IDO expression by the tumor cells.

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Journal of Experimental Medicine

Tập 210 Số 7

1389-1402

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