Roles of regulatory T cells in cancer immunity

Abstract

CD4(+) regulatory T cells (Tregs) 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 Tregs is observed in tumor tissues, and their depletion augments antitumor immune responses in animal models. Additionally, increased numbers of Tregs and, in particular, decreased ratios of CD8(+) T cells to Tregs 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 Treg-mediated suppression. Thus, integration of a strategy restricting Treg-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 Treg-mediated immune suppressive mechanisms in cancer, the involvement of Tregs in cancer immunotherapy, and strategies for effective and tolerable Treg-targeted therapy.

Keywords: Treg-targeted therapy; immune checkpoint inhibitors; immune suppression.

Fig. 1.

Identification of human T_regs. Human T_regs are classified into naive and effector T_regs by the expression levels of a naive marker CD45RA and of FoxP3. In TMEs compared with blood, naive T_reg (fraction I, Fr. I) numbers are reduced and highly suppressive effector T_reg (fraction II) numbers are increased, expressing CTLA-4, PD-1, TIM-3 and CCR4. The frequency of FoxP3⁺ non-T_reg cells (fraction III) is variable depending on cancer types.

Fig. 2.

T_regs in cancer immunity. In cancer patients with minimal neoantigens (top part of the figure), T_regs appear to be primed at the secondary lymphoid organs and traffic to the TME by chemotaxis. T_regs suppress effective antitumor immunity and/or contribute to tumor progression and metastasis. In contrast, in cancer patients with abundant neoantigens (bottom part of the figure), effector cells including CD8⁺ T cells are primed and expanded; while they are suppressed in local tumor sites by the immune suppressive network and chronic exposure to cancer antigens in tumors, they are yet on stand-by for tumor killing upon re-stimulation with inhibition of the immune suppressive network, particularly PD-1 signaling. Grz, granzyme; MDSC, myeloid-derived suppressor cell; Prf, perforin; T_R, regulatory T cell.