Regulatory T cells in tumor microenvironment: new mechanisms, potential therapeutic strategies and future prospects

Abstract

Regulatory T cells (Tregs) characterized by the expression of the master transcription factor forkhead box protein p3 (Foxp3) suppress anticancer immunity, thereby hindering protective immunosurveillance of tumours and hampering effective antitumour immune responses in tumour-bearing hosts, constitute a current research hotspot in the field. However, Tregs are also essential for the maintenance of the immune tolerance of the body and share many molecular signalling pathways with conventional T cells, including cytotoxic T cells, the primary mediators of tumour immunity. Hence, the inability to specifically target and neutralize Tregs in the tumour microenvironment without globally compromising self-tolerance poses a significant challenge. Here, we review recent advances in characterizing tumour-infiltrating Tregs with a focus on the functional roles of costimulatory and inhibitory receptors in Tregs, evaluate their potential as clinical targets, and systematically summarize their roles in potential treatment strategies. Also, we propose modalities to integrate our increasing knowledge on Tregs phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Finally, we propose possible treatment strategies that can be used to develop Treg-targeted therapies.

The Functional Crosstalk between Myeloid-Derived Suppressor Cells and Regulatory T Cells within the Immunosuppressive Tumor Microenvironment

“…It has been shown that regulatory T cells play a crucial role in regulating the homeostasis of the immune system and maintaining tolerance [ 130 ]. Moreover, Treg have been found to limit the anti-tumor immune response.…”

“…Treg are defined as a T helper cell subpopulation characterized by the co-expression of CD4, CD25, and in large parts of FoxP3, which inhibit the activation and differentiation of CD4 + and CD8 + T cells, subsequently impairing reactivity against autologous and tumor-expressed antigens [ 130 , 133 , 134 ]. According to their biological properties, Treg are generally divided into two groups: natural (n) regulatory T cells and induced (i) regulatory T cells, which commonly express FoxP3 [ 135 ].…”

Senescent Tumor CD8+ T Cells: Mechanisms of Induction and Challenges to Immunotherapy

“…IL-35 and IL-10 promote T cell exhaustion. Metabolic competition for the consumption of IL-2 through the expression of CD25 on Tregs also suppresses T c effector functions [ 33 ]. Tregs are also found in peripheral circulation, but their precise role in facilitating immune evasion are not as well characterized as with the TME-associated Tregs [ 32 ].…”

“…Other immune cells within the TME might also indirectly impact T c senescence. Treg and MDSC populations often support each other’s expansion through positive feedback loops involving TGF-β and other cytokines [ 33 ]. In turn, MDSCs can be expanded by many of the SASP cytokines secreted by T c senescent cells such as TGF-β, IL-6 and IFN-γ [ 39 ].…”

Overexpressed Pseudogene MT1L Associated with Tumor Immune Infiltrates and Indicates a Worse Prognosis in BLCA

“…Tregs and MDSCs are key regulators of antitumor responses in BLCA, and the intra-tumoral presence of those are correlated with the poor clinical outcome has already been established[30,31]. Tregs serve as a vital immunosuppressive factor to promote tumor occurrence and development, inhibit antitumor immunity, and help in tumor immune escape[32]. Likewise, MDSCs are widely distributed and have strong immunosuppressive activity in the TME that inhibit cytotoxic T cells' proliferation and activation, leading to the failure of the antitumor immune response and promoting cancer progression and chemoresistance[33].…”