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Indoleamine 2,3-dioxygenase is a critical resistance mechanism in anti-tumor T cell immunotherapy targeting CTLA-4
  1. Rikke B Holmgaard1,
  2. Dmitriy Zamarin1,
  3. David H Munn3,
  4. Jedd D Wolchok1 and
  5. James P Allison1,2
  1. Aff1 grid.51462.340000000121719952Department of ImmunologyMemorial Sloan-Kettering Cancer Center New York NY USA
  2. Aff2 grid.240145.60000000122914776Department of ImmunologyMD Anderson Cancer Center Houston TX USA
  3. Aff3 grid.410427.40000000419370183Cancer Center and Department of PediatricsGeorgia Regents University Augusta GA USA

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Meeting abstracts

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.