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

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          Abstract

          Indoleamine 2,3-dioxygenase suppresses infiltration and accumulation of tumor-reactive T cells in the context of anti–CTLA-4 immunotherapy and attenuates the anti-tumor efficacy.

          Abstract

          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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          Author and article information

          Journal
          J Exp Med
          J. Exp. Med
          jem
          The Journal of Experimental Medicine
          The Rockefeller University Press
          0022-1007
          1540-9538
          1 July 2013
          : 210
          : 7
          : 1389-1402
          Affiliations
          [1 ]Howard Hughes Medical Institute, Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
          [2 ]Swim Across America Laboratory/Ludwig Collaborative Research Laboratory, Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, NY 10065
          [3 ]Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065
          [4 ]Cancer Center and Department of Pediatrics, Georgia Regents University, Augusta, GA 30912
          [5 ]Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University, New York, NY 10065
          [6 ]Ludwig Institute for Cancer Research, New York, NY 10065
          [7 ]The University of Texas, MD Anderson Cancer Center, Department of Immunology, Houston, TX 77030
          Author notes
          CORRESPONDENCE Rikke B. Holmgaard: HolmgaaR@ 123456mskcc.org OR James P. Allison: jallison@ 123456mdanderson.org
          Article
          20130066
          10.1084/jem.20130066
          3698523
          23752227
          © 2013 Holmgaard et al.

          This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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