Regulatory T cells in cancer anti-PD-(L)1 therapy

Regulatory T cell (Treg) immunome profile and targets in antiprogrammed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) is a subject of extensive research, but there are still complexities in the area due to the nature of tumor microenvironment (TME). TME of solid tumors contains factors exerting a range of effects on Tregs including development, recruitment, expansion, stability and their immunosuppressive activity. Anti-PD-1 secondarily causes replenishment of intratumoral Tregs, which further intensify tumor immunosuppression. Besides, Treg depletion may also compromise immune checkpoint inhibitor (ICI) efficacy in addition to its other adversarial effects. Thus, a desired ICI booster is to use agents preferentially acting on intratumoral Tregs. Modulation of hypoxia, and regulation of Treg-related cytokines, chemokines, receptors and chromatin modifying factors in tumor TME provide supplementary approaches to anti-PD-(L)1. Factors acting on Tregs have diverse or even dual functions in TME. Treg expansion inhibitory and immunosuppressive tumor-associated macrophage (TAM) recruitment stimulatory effects of stimulator of interferon genes (STING), effector suppressor Treg activating and tumor-specific CD8⁺ T cell stimulatory effects of interleukin type 2 receptor alpha (IL-2Rα, also called CD25), cell type-dependent dual activities of CXCR3 and inducible T cell costimulatory (ICOS), exposure time-dependent dual effects of glucocorticoid-induced TNFR-related protein (GITR) and CD70 on Tregs and T cells, and exposure level-dependent dual activities of IFN-γ on Tregs are examples require consideration in designing Treg-based strategies. The main direction of this review is to provide updated information about targeting modulators of intratumoral Tregs with agents/compounds aiming to expand anti-PD-(L)1 efficacy and durability in solid tumors.