Suppression, subversion and escape: the role of regulatory T cells in cancer progression

Abstract

Regulatory T cells (T(regs) ) are crucial in mediating immune homeostasis and promoting the establishment and maintenance of peripheral tolerance. However, in the context of cancer their role is more complex, and they are thought to contribute to the progress of many tumours. As cancer cells express both self- and tumour-associated antigens, T(regs) are key to dampening effector cell responses, and therefore represent one of the main obstacles to effective anti-tumour responses. Suppression mechanisms employed by T(regs) are thought to contribute significantly to the failure of current therapies that rely on induction or potentiation of anti-tumour responses. This review will focus on the current evidence supporting the central role of T(regs) in establishing tumour-specific tolerance and promoting cancer escape. We outline the mechanisms underlying their suppressive function and discuss the potential routes of T(regs) accumulation within the tumour, including enhanced recruitment, in-situ or local proliferation, and de-novo differentiation. In addition, we review some of the cancer treatment strategies that act, at least in part, to eliminate or interfere with the function of T(regs) . The role of T(regs) is being recognized increasingly in cancer, and controlling the function of these suppressive cells in the tumour microenvironment without compromising peripheral tolerance represents a significant challenge for cancer therapies.

Fig. 1

Down-modulation of anti-tumour immune responses. Mechanisms for down-regulating anti-tumour immune responses can be categorized into tumour-intrinsic (left panel) and tumour-extrinsic (right panel). The first includes secretion of immunosuppressive cytokines or other soluble factors, alteration of immunogenicity and deletion or manipulation of tumour-associated antigen-specific effector cell function by the tumour cells or surrounding parenchyma. Tumour-intrinsic immunosuppressive mechanisms include secretion of immunosuppressive cytokines [interleukin (IL)-10 and transforming growth factor (TGF)-β], growth factors [vascular endothelial growth factor (VEGF)], or enzymes [indoleamine 2,3-dioxygenase (IDO)] and expression of inhibitory cell-surface molecules such as programmed cell death ligand (PD-L), Fas ligand (Fas-L), the co-inhibitory receptor B7 homologue 3 (B7-H3) and non-classical human leucocyte antigen (HLA) molecules (HLA-E/G). Tumour-intrinsic mechanisms promote a microenvironment that enhances regulatory T cell (T_reg) function. Extrinsic mechanisms involve a range of suppressive cells including suppressive T cells (inducible and natural T_regs and Tr1 T cells) and a heterogeneous population of myeloid-derived suppressor cells (MDSCs), alternatively activated M2-like tumour-associated macrophages (TAMs), immature antigen-presenting cells (APCs) and plasmacytoid dendritic cells (pDCs). The cells exert their effects via both interaction with infiltrating anti-tumour inflammatory cells and contribution to the suppressive tumour microenvironment.

Fig. 2

Mechanisms of regulatory T cell-mediated suppression. Regulatory T cells (T_regs) can mediate suppression through their effects on dendritic cells (DCs), such as physical inhibition of interaction between DCs and conventional T cells (T_conv) or deprivation of co-stimulation or soluble factors. Cytotoxic T lymphocyte-associated antigen (CTLA)-4 on T_regs interacts with CD80 and CD86 on DC with high affinity. In addition to inhibiting co-stimulation via CD28 on T_conv, this can lead to down-regulation of CD80 and CD86 expression on the DC (either through transendocytosis or transcriptional regulation), thereby further reducing their co-stimulatory capacity and T_conv activation and proliferation. It can also lead to up-regulation of indolamine 2,3-dioxygenase (IDO) in DC, which can mediate suppression of T_conv by tryptophan depletion and apoptosis through tryptophan catabolites. Perforin and granzyme B from T_regs induces apoptosis and cytolysis of both T_conv and DC. Deprivation of interleukin (IL)-2 via the high-affinity IL-2 receptor (haIL-2R, consisting of a CD25, CD122, CD132 complex) and adenosine triphosphate (ATP) through CD39 and CD73 can lead to the inhibition of T_conv activation or T cell apoptosis. The cytokines IL-10 and IL-35 can mediate suppression, and IL-35 can also act as an autocrine T_reg growth factor. While secreted TGF-β induces IDO in DCs, how much the cytokine contributes to T_reg-mediated suppression is under debate. Cyclic adenosine monophosphate (cAMP) transferred to T_conv via gap junctions inhibits their IL-2 production and subsequent proliferation. A number of other suppression mechanisms have been proposed. The relative contributions of these processes remain to be determined. Generally, spatiotemporal context may determine which of these mechanisms dominate. CD39: nucleoside triphosphate diphosphohydrolase; CD73: ecto-5′-nucleotidase.