Human regulatory T cells (Treg) and their response to cancer.

INTRODUCTION: Regulatory T cells (Treg) and their role in health and disease is being intensively investigated. Today, human Treg emerge as a highly heterogeneous subset of CD4+ T cells which mediate immune suppression but also regulate responses of non-immune cells. In cancer, Treg occupy a critical although not yet entirely understood role. AREAS COVERED: Newly acquired insights into Treg indicate a much greater plasticity and functional heterogeneity of this T cell subset than was previously known. Functional redundancy of Treg and their interactions with a variety of immune and non-immune cellular targets emphasize the central role Treg play in cancer. Treg not only regulate the host responses to cancer; they may also regulate responses to immune therapies. The impact of immune checkpoint blockade on Treg survival, stability and suppressive activity remains to be elucidated. T cell reprogramming by tumor-derived factors, including tumor-derived exosomes (TEX), plays a key role in shaping the Treg repertoire in the tumor microenvironment (TME). The reprogrammed or induced iTreg acquire capabilities to strongly down-regulate anti-tumor immune responses by mechanisms that are specific for each TME. Therapeutic silencing of such Treg calls for the discrimination of "bad" from "good" Treg subsets, an approach that remains elusive in the absence of a definitive "Treg signature." EXPERT OPINION: Context-related plasticity and heterogeneity of Treg in the TME are significant barriers to selective therapeutic depletion of those Treg subsets that are reprogramed by the tumor to suppress anti-tumor immunity.