Intratumoral regulatory T cells: markers, subsets and their impact on anti-tumor immunity

Abstract

Regulatory T (Treg) cells play a crucial role in maintaining self-tolerance and resolution of immune responses by employing multifaceted immunoregulatory mechanisms. However, Treg cells readily infiltrate into the tumor microenvironment (TME) and dampen anti-tumor immune responses, thereby becoming a barrier to effective cancer immunotherapy. There has been a substantial expansion in the development of novel immunotherapies targeting various inhibitory receptors (IRs), such as CTLA4, PD1 and LAG3, but these approaches have mechanistically focused on the elicitation of anti-tumor responses. However, enhanced inflammation in the TME could also play a detrimental role by facilitating the recruitment, stability and function of Treg cells by up-regulating chemokines that promote Treg cell migration, and/or increasing inhibitory cytokine production. Furthermore, IR blockade may enhance Treg cell function and survival, thereby serving as a resistance mechanism against effective immunotherapy. Given that Treg cells are comprised of functionally and phenotypically heterogeneous sub-populations that may alter their characteristics in a context-dependent manner, it is critical to identify unique molecular pathways that are preferentially used by intratumoral Treg cells. In this review, we discuss markers that serve to identify certain Treg cell subsets, distinguished by chemokine receptors, IRs and cytokines that facilitate their migration, stability and function in the TME. We also discuss how these Treg cell subsets correlate with the clinical outcome of patients with various types of cancer and how they may serve as potential TME-specific targets for novel cancer immunotherapies.

Keywords: chemokine/chemokine receptors; cytokines; inhibitory/activating receptors; regulatory T cells; tumor immunology.

Figure 1

Subset stratification of intratumoral regulatory T (Treg) cells. Heterogeneous intratumoral Treg cells can be characterized based on their expression pattern on functional surface molecules or secretion of inhibitory cytokines. Activated Treg cells up‐regulate various chemokine receptors in a context‐dependent manner to home to the site of inflammation. Some chemokine receptors, such as CCR8, have been shown to also support Treg function and stability in addition to providing chemotactic navigation to guide Treg cells to the tumor microenvironment (TME). Furthermore, Treg cells also up‐regulate numerous inhibitory receptors (IRs), including PD1 and LAG3. Although many of these IRs have been associated with dysfunctional, exhausted CD8⁺ tumor‐infiltrating lymphocytes (TILs), the exact cell‐intrinsic role(s) of IRs in intratumoral Treg cells have not been fully elucidated. Some IRs, such as TIGIT, maintain and promote the suppressive function of Treg cells, whereas other IRs, including PD1 and LAG3, have been associated with a reduced suppressive activity of Treg cells. Lastly, there are divergent subpopulations of intratumoral Treg cells secreting different inhibitory cytokines, such as transforming growth factor‐β (TGF‐β), interleukin‐10 (IL‐10) and IL‐35.