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Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2013 Jul 01; Vol. 210 (7), pp. 1389-402. Date of Electronic Publication: 2013 Jun 10. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Antibodies, Monoclonal administration & dosage
Antibodies, Monoclonal therapeutic use
CTLA-4 Antigen immunology
Cell Line, Tumor
Enzyme Inhibitors administration & dosage
Enzyme Inhibitors therapeutic use
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase antagonists & inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase deficiency
Ipilimumab
Lymphocytes, Tumor-Infiltrating immunology
Lymphocytes, Tumor-Infiltrating pathology
Melanoma, Experimental enzymology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
T-Lymphocyte Subsets enzymology
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets pathology
CTLA-4 Antigen antagonists & inhibitors
Immunotherapy
Indoleamine-Pyrrole 2,3,-Dioxygenase physiology
Melanoma, Experimental immunology
Melanoma, Experimental therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 210
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23752227
- Full Text :
- https://doi.org/10.1084/jem.20130066