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Review
. 2020 Jul 17;19(1):116.
doi: 10.1186/s12943-020-01234-1.

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

Chunxiao Li  1 , Ping Jiang  2 , Shuhua Wei  2 , Xiaofei Xu  3   4 , Junjie Wang  5
Affiliations
Review

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

Chunxiao Li et al. Mol Cancer. .

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.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
The differentiation of Tregs in tumor from naïve T cell in thymus through circulation. Treg is derived from peripheral naive T cells induced by tumor microenvironmental signals, including tumor antigens, cytokines (such as TGF-β) and some metabolic factor, which are concluded now. Furthermore, these promotion and inhibition factors are explained in this review
Fig. 2
Fig. 2
Effects of Tregs on the immune cells. The mechanism mainly includes four aspects:①secreting inhibitory cytokines, including IL-10, TGF-β, IL-35 etc., eg. inhibiting immune function through il-10 and other dependent ways, and Treg can also inhibit CD8+ T cells and DCs through membrane-bound TGF-β, thereby regulating the body‘s anti-tumor immune function. ②killing effector cells by granulase and perforin. Granzyme and perforin are the main molecules that mediate the cytotoxicity of CTL, NK and other cells.③Tregs affect effector cell function by interfering with cell metabolism mainly in the following three ways:(1) Deprivation of IL-2 in the TME, and the growth of Tregs and effector T cells requires the maintenance of IL-2. (2) CD39 and CD73 are nucleases that are constitutionally expressed in human and mouse Tregs. They can hydrolyse extracellular ATP or ADP into AMP and produce Adenosine. Tregs promotes the production of adenosine in the TME by producing the extracellular enzymes CD39 and CD73, and produces inhibitory and anti-proliferative effects by binding to the adenosine receptor A2A on the surface of effector cells. (3) Treg transferred a large number of cAMP to effector T cells through gap junction to interfere with their metabolism. ④Affect the differentiation and proliferation of Tregs by regulating DCs. The Tregs-expressed CTLA-4 was combined with CD80 and CD86 on the surface of DCs to downregulate the synergistic stimulus signal. Lymphocyte activation gene 3 (LAG3) molecules expressed by Tregs can inhibit the expression of MHC II molecules in DCs. DCs tolerance can be induced by the above two methods, and the latter can further induce T cell incapacity by IDOc. ⑤There exist the functional crosstalk between Tregs and MDSCs. Factors produced by both MDSCs and Tregs form positive feedback loops to facilitate the expansion of each population and reinforce the suppressive environment. On the one hand, MDSCs promoted the induction of Tregs through producing molecules including TGF-β, IL10, CD73, and IDO. On the other hand, Tregs can also modulate MDSCs expansion and function through secreting IL-35 and TGF-β. Additionally, cell-surface molecular interactions can promote the function of both MDSC and Tregs, including CD40/CD40L, PD-1/PD-L1, and CD80/CTLA-4
Fig. 3
Fig. 3
New classifications of Tregs. Th-like Tregs are Th1-like Tregs (T-bet+IFNγ+Foxp3+), Th2-like Tregs (Gata3 + IRF4 + IL4 + Foxp3+) and Th17-like Tregs (IL-17+ RORγt+Foxp3+)
Fig. 4
Fig. 4
Metabolic regulation of Foxp3 expression. Environmental metabolites, intracellular metabolic intermediates and signaling pathways all regulate Foxp3 expression in Tregs. LKB1 prevents STAT4 activation and binding to CNS2 of Foxp3 gene, thus preventing the destabilization effect. E3 ubiquitin ligase VHL can regulate HIF-1α to maintain the stability and suppressive capacity of Tregs. Foxp3 opposed PI3K-Akt-mTORC1 signaling to decrease glycolysis and anabolic metabolism while increasing oxidative and catabolic metabolism. CD36 finetuned mitochondrial fitness via peroxisome proliferator-activated receptor-beta (PPARβ) signaling, programming Tregs to adapt to a lactic acidenriched TME. The deletion of TRAF6 in Tregs were resistant to implanted tumors and displayed enhanced antitumor immunity due to that Foxp3 undergoes K63-linked ubiquitination at lysine 262 mediated by the E3 ligase TRAF6. The specific ablation of RagA-RagB or Rheb1Rheb2 in Tregs has reduced Tregs accumulation and function. RagA-RagB regulated mitochondrial and lysosomal fitness, while Rheb1Rheb2 enforced Tregs suppressive gene signature licensed by amino acids. YAP-dependent upregulate activin signaling, which amplifies TGFβ/SMAD activation in Tregs. TAZ attenuated Tregs development by decreasing acetylation of Foxp3 mediated by the histone acetyltransferase Tip60. TEAD1 expression and sequestration of TAZ from the transcription factors Foxp3 promotes Tregs differentiation. TLR8 signaling selectively inhibits glucose uptake and glycolysis in human Tregs, resulting in reversal of Tregs suppression. Mst1promote Tregs migration and access to IL-2 and activity of the small GTPase Rac, which mediated downstream STAT5 activation. Mst1-Mst2 sensed IL-2 signals to promote the STAT5 activation necessary for Tregs homeostasis and lineage stability and to maintain the highly suppressive pSTAT5+Tregs
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