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

RB Holmgaard, D Zamarin, DH Munn… - Journal of Experimental …, 2013 - rupress.org
RB Holmgaard, D Zamarin, DH Munn, JD Wolchok, JP Allison
Journal of Experimental Medicine, 2013rupress.org
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 …
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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