The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4
Open accessAbstract
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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Cites
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“…found in primary melanoma and draining lymph nodes (Munn et al., 2004; Polak et al., 2007; Brody et al., 2009), and its presence has been shown to correlate with tumor progression and invasiveness (Munn et al., 2004; Lee et al., 2005; Harlin et al., 2006; Polak et al., 2007; Weinlich et al., 2007).”
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Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond
Platten, M., Nollen, E. A. A., Röhrig, U. F., Fallarino, F., & Opitz, C. A. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-019-0016-5 · Cited by 1,586
Metadata
- Authors
- Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D., & Allison, J. P.
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2013-06-10
- Volume
- 210
- Issue
- 7
- Pages
- 1389-1402
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- OpenAlex
- W2126932404
- Cited by
- 634
- References
- 14
- FWCI
- 25.14
- Type
- journal article
- Language
- en
- Open access
- bronze
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- Holmgaard, R. B., Zamarin, D., Munn, D. H., Wolchok, J. D., & Allison, J. P. (2013). Indoleamine 2,3-dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy targeting CTLA-4. Journal of Experimental Medicine. https://doi.org/10.1084/jem.20130066
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Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
