Roles of regulatory T cells in cancer immunity

CD4(+) regulatory T cells (T-regs) expressing the transcription factor FoxP3 are highly immune suppressive and play central roles in the maintenance of self-tolerance and immune homeostasis, yet in malignant tumors they promote tumor progression by suppressing effective antitumor immunity. Indeed, higher infiltration by T-reg is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of T-reg and, in particular, decreased ratios of CD8(+) T cells to T-reg among tumor-infiltrating lymphocytes are correlated with poor prognosis in various types of human cancers. The recent success of cancer immunotherapy represented by immune checkpoint blockade has provided a new insight in cancer treatment, yet more than half of the treated patients did not experience clinical benefits. Identifying biomarkers that predict clinical responses and developing novel immunotherapies are therefore urgently required. Cancer patients whose tumors contain a large number of neoantigens stemming from gene mutations, which have not been previously recognized by the immune system, provoke strong antitumor T-cell responses associated with clinical responses following immune checkpoint blockade, depending on the resistance to T-reg-mediated suppression. Thus, integration of a strategy restricting T-reg-mediated immune suppression may expand the therapeutic spectrum of cancer immunotherapy towards patients with a lower number of neoantigens. In this review, we address the current understanding of T-reg-mediated immune suppressive mechanisms in cancer, the involvement of T regs in cancer immunotherapy, and strategies for effective and tolerable T-reg-targeted therapy.