Regulation of regulatory T cells in cancer

Abstract

The inflammatory response to transformed cells forms the cornerstone of natural or therapeutically induced protective immunity to cancer. Regulatory T (Treg) cells are known for their critical role in suppressing inflammation, and therefore can antagonize effective anti-cancer immune responses. As such, Treg cells can play detrimental roles in tumour progression and in the response to both conventional and immune-based cancer therapies. Recent advances in our understanding of Treg cells reveal complex niche-specific regulatory programmes and functions, which are likely to extrapolate to cancer. The regulation of Treg cells is reliant on upstream cues from haematopoietic and non-immune cells, which dictates their genetic, epigenetic and downstream functional programmes. In this review we will discuss how Treg cells are themselves regulated in normal and transformed tissues, and the implications of this cross talk on tumour growth.

Keywords: cancer; chemokine/chemokine receptors; cytokines/cytokine receptors; regulatory T cells; tumour immunology.

Figure 1

Origin of regulatory T (Treg) cells in tumours. Depicted are the three scenarios – not mutually exclusive – that could account for the presence of Treg cells within tumours. Left, conversion of naive CD4⁺ T cells into peripheral Treg (pTreg) cells; centre, recruitment of thymus‐derived Treg (tTreg) cells from the circulation; right, expansion of tissue‐resident Treg cells.

Figure 2

Co‐stimulatory, co‐inhibitory and cytokine receptors expressed by regulatory T (Treg) cells in tumours. Co‐stimulatory (left) and co‐inhibitory (middle) molecules, as well as cytokine receptors (right), deliver signals to Treg cells following engagement by their ligands expressed by immune and/or non‐immune cell types within the tumour. Positive and negative signs in the Treg cell indicate either a positive effect on proliferation (Prolif.) or function (Funct.) or an inhibitory effect (i.e. reduced function), respectively, after receptor engagement. Question marks (?) indicate that the outcome of the receptor engagement in the Treg cell warrants further investigation.