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Targeting multiple inhibitory receptors to reverse melanoma-induced T cell dysfunction

It is now clearly established that dysfunctional/exhausted TA-specific T cells present in peripheral blood and at tumor sites co-express multiple inhibitory receptors. The implications of this important finding are two-fold. First, multiple subsets of TA-specific T cells can be identified in patients with advanced melanoma that exhibit variable levels of T cell dysfunction. Second, this observation supports the implementation of combinatorial therapies aiming at blocking multiple inhibitory pathways to enhance TA-specific immune responses and reverse tumor-induced T cell dysfunction. We have shown that a subset of highly dysfunctional TA-specific CD8+ T cells isolated from patients with advanced melanoma upregulate both PD-1 and Tim-3. PD-1 and Tim-3 blockades strongly enhance TA-specific CD8+ T cell expansion and function. Accordingly, targeting PD-1 and Tim-3 in vivo induces melanoma regression in mice. Therefore, the combination of PD-1 and Tim-3 blockade either alone or in combination with cancer vaccines appears to be a promising potent approach to reverse melanoma-induced T cell dysfunction and promote tumor regression in patients with advanced melanoma.

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Correspondence to Hassane M Zarour.

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Zarour, H.M. Targeting multiple inhibitory receptors to reverse melanoma-induced T cell dysfunction. J Transl Med 13, K14 (2015). https://doi.org/10.1186/1479-5876-13-S1-K14

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Keywords

  • Immune Response
  • Melanoma
  • Variable Level
  • Tumor Site
  • Tumor Regression