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Indoleamine 2,3-dioxygenase is a critical resistance mechanism in anti-tumor T cell immunotherapy targeting CTLA-4
© Holmgaard et al; licensee BioMed Central Ltd. 2013
Published: 7 November 2013
The 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. We examine the inhibitory role of indoleamine 2,3-dioxygenase (IDO) on the anti-tumor 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 to wild type mice. 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 non-expressing 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 anti-CTLA-4 immunotherapy and provide a strong incentive to clinically explore combination therapies utilizing IDO inhibitors irrespective of IDO expression by the tumor cells.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.