Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 Journal Article
| Authors: | Holmgaard, R. B.; Zamarin, D.; Munn, D. H.; Wolchok, J. D.; Allison, J. P. |
| Article Title: | Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4 |
| 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. ©2013 Holmgaard et al. |
| Keywords: | controlled study; unclassified drug; overall survival; drug potentiation; nonhuman; cd8+ t lymphocyte; t lymphocyte; lymphocytes, tumor-infiltrating; animal cell; mouse; animals; mice; mice, knockout; animal tissue; cytotoxic t lymphocyte antigen 4 antibody; cancer immunotherapy; melanoma; animal experiment; animal model; antineoplastic activity; cell line, tumor; tumor antigen; mice, inbred balb c; mice, inbred c57bl; regulatory t lymphocyte; antibodies, monoclonal; immunotherapy; gamma interferon; enzyme inhibitors; immunogenicity; breast tumor; cd4+ t lymphocyte; melanoma, experimental; effector cell; t-lymphocyte subsets; indoleamine 2,3 dioxygenase; indoleamine-pyrrole 2,3,-dioxygenase; tumor growth; lymphocytic infiltration; cytotoxic t lymphocyte antigen 4; glucocorticoid induced tumor necrosis factor receptor; tumor rejection; programmed death 1 ligand 1; programmed death 1 receptor; indoleamine 2,3 dioxygenase inhibitor; ctla-4 antigen; 1 methyl tryptophan |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 210 |
| Issue: | 7 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2013-07-01 |
| Start Page: | 1389 |
| End Page: | 1402 |
| Language: | English |
| DOI: | 10.1084/jem.20130066 |
| PROVIDER: | scopus |
| PMCID: | PMC3698523 |
| PUBMED: | 23752227 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 4 September 2013" - "CODEN: JEMEA" - "Source: Scopus" |
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