Regulatory T cells—an important target for cancer immunotherapy

We appreciate very much the correspondence from Shin & Ha regarding an important role for regulatory T cells (T_REG) 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 T_REG 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 T_REG of patients with cancer remains unclear. Whereas two recent animal studies^3,4 showed that anti-CTLA-4 antibodies can deplete T_REG 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 T_REG 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 T_REG;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 T_REG manipulation is that there are still no extracellular molecules absolutely specific to T_REG; the vast majority of these molecules are, in fact, expressed on activated CD4 T cells as well. Furthermore, targeting T_REG 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 T_REG—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.