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.
Highlights
Regulatory T cells (Tregs), as an important mechanism for regulating homeostasis of the immune system and the immune tolerance of the body, play crucial roles in the regulation of tumour immunity and constitute a current research hotspot in the field, primarily as potential targets (Supplementary Table 1) that can inhibit the activation and differentiation of CD4+ helper T cells and CD8+ cytotoxic T cells to induce reactivity against autologous and tumour-expressed antigens [1–3]
Due to the production of cytokines, chemokines, and foreign body-mediated reprogramming in the tumour microenvironment, the functional evaluation of Tregs in tumour tissues is complex and difficult to determine
Tumour immunotherapy targeting Tregs mainly focused on clearance, but the effect was not ideal
Summary
Regulatory T cells (Tregs), as an important mechanism for regulating homeostasis of the immune system and the immune tolerance of the body, play crucial roles in the regulation of tumour immunity and constitute a current research hotspot in the field, primarily as potential targets (Supplementary Table 1) that can inhibit the activation and differentiation of CD4+ helper T cells and CD8+ cytotoxic T cells to induce reactivity against autologous and tumour-expressed antigens [1–3]. Tregs promote the production of adenosine in the TME by producing the extracellular enzymes CD39 and CD73 and induce inhibitory and anti-proliferative effects by binding to the adenosine receptor A2A on the surface of effector cells [51] (Fig. 2). TLR8 signalling-mediated reprogramming of glucose metabolism and function in human Tregs can enhance antitumour immunity in vivo in a melanoma adoptive transfer T cell therapy model [99].
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