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Regulatory T cells—an important target for cancer immunotherapy

Nature Reviews Clinical Oncology volume 11, page 307 (2014)Cite this article

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We appreciate very much the correspondence from Shin & Ha regarding an important role for regulatory T cells (TREG) in antitumour immunity (Regulatory T cells—an important target for cancer immunotherapy. Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.208-c1),1 and their suggestion that this topic was somewhat neglected in our recent Review on cancer immunotherapy (Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat. Rev. Clin. Oncol. 11, 24–37 [2014]).2 In their thoughtful letter, they highlight several murine and human in vitro studies suggesting that manipulation of TREG number and/or function may be an important consequence of immune checkpoint blockade. In that regard, we concur completely with their assessment that the effects of CTLA-4 blockade in regulating TREG of patients with cancer remains unclear. Whereas two recent animal studies3,4 showed that anti-CTLA-4 antibodies can deplete TREG that express relatively high levels of CTLA-4, the clinical relevance of these data is slightly undermined by the clinical observation that polymorphisms of human Fc receptors (FcRs) did not seem to correlate with the efficacy of anti-CTLA-4 in a fairly large series of patients with melanoma; such a correlation might be expected if FcR-mediated TREG depletion was the major mechanism by which this agent functions.5 In vitro studies of human T cells treated with anti-PD-1 or anti-PD-L1 antibodies showed a decreased expression of FOXP3 in TREG;6 however, to our knowledge these findings have not yet been replicated in vivo or in patients treated with monoclonal antibodies to PD-1 and/or PD-L1 in clinical trials. Perhaps the most important challenge in cancer immunotherapy involving TREG manipulation is that there are still no extracellular molecules absolutely specific to TREG; the vast majority of these molecules are, in fact, expressed on activated CD4 T cells as well. Furthermore, targeting TREG with antibodies directed against C-C chemokine receptor type (CCR-4)7 or even to lymphocyte activation gene 3 protein (LAG-3)8 is a viable clinical strategy; however, these approaches are in a relatively earlier stage of development compared to the immune checkpoint and vaccine regimens discussed in our Review.

Nevertheless, we are in complete concurrence with Shin & Ha that a combined immunotherapy regimen—which includes specific targeting of TREG—represents a promising strategy, particularly for either advanced-stage disease or for the many tumour types that have not shown objective responses to single-agent immune checkpoint blockade.

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References

  1. Shin, J. I. & Ha, S.-J. Regulatory T cells—an important target for cancer immunotherapy. Nat. Rev. Clin. Oncol. http://dx.doi:10.1038/nrclinonc.2013.208-c1.

  2. Drake, C. G., Lipson, E. J. & Brahmer, J. R. Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer. Nat. Rev. Clin. Oncol. 11, 24–37 (2014).

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  1. Department of Oncology, Johns Hopkins University, 1650 Orleans Street, Baltimore, 21231, MD, USA

    Charles G. Drake, Evan J. Lipson & Julie R. Brahmer

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  1. Charles G. Drake
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  2. Evan J. Lipson
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Correspondence to Charles G. Drake.

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Competing interests

C. G. D. has served as a paid consultant to BMS, CoStim Pharmaceuticals, Dendreon, and Pfizer Inc. J. R. B. has served as an unpaid advisory board member to BMS and a paid consultant for Merck. E. J. L. declares no competing interests.

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Drake, C., Lipson, E. & Brahmer, J. Regulatory T cells—an important target for cancer immunotherapy. Nat Rev Clin Oncol 11, 307 (2014). https://doi.org/10.1038/nrclinonc.2013.208-c2

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