Lipid metabolism in tumor-infiltrating regulatory T cells: perspective to precision immunotherapy

Abstract

Regulatory T cells (Tregs) are essential to the negative regulation of the immune system, as they avoid excessive inflammation and mediate tumor development. The abundance of Tregs in tumor tissues suggests that Tregs may be eliminated or functionally inhibited to stimulate antitumor immunity. However, immunotherapy targeting Tregs has been severely hampered by autoimmune diseases due to the systemic elimination of Tregs. Recently, emerging studies have shown that metabolic regulation can specifically target tumor-infiltrating immune cells, and lipid accumulation in TME is associated with immunosuppression. Nevertheless, how Tregs actively regulate metabolic reprogramming to outcompete effector T cells (Teffs), and how lipid metabolic reprogramming contributes to the immunomodulatory capacity of Tregs have not been fully discussed. This review will discuss the physiological processes by which lipid accumulation confers a metabolic advantage to tumor-infiltrating Tregs (TI-Tregs) and amplifies their immunosuppressive functions. Furthermore, we will provide a summary of the driving effects of various metabolic regulators on the metabolic reprogramming of Tregs. Finally, we propose that targeting the lipid metabolism of TI-Tregs could be efficacious either alone or in conjunction with immune checkpoint therapy.

Keywords: Immunosuppression; Lipid metabolism; Metabolic competition; Metabolic regulatory switches; Tregs; Tumor therapies.

Fig. 1

Overview of tregs. In inflamed tissues, exposure to the contents of necrotic cells induces massive infiltration of inflammatory cells to initiate the inflammatory response. During this process, Tregs that constitutively express CTLA-4, IL-2Ra, etc., are also recruited to mediate immunosuppression and prevent excessive activation of inflammation. In the tumor microenvironment(TME), the massive accumulation of lipids promotes the survival and immunosuppressive function of Tregs, leading to dysfunction of anti-tumor immune and resistance to immunotherapy. ICI: immune checkpoint inhibitor; Tregs: Regulatory T cells

Fig. 2

Lipid metabolism enhances treg-mediated immunosuppression. Lipid metabolism is conducive to the expression of PD-1, CTLA-4, ICOS, and FOXP3 in Tregs, enhancing immunosuppressive ability. Free fatty acids uptake enhances FAO through activating the PPAR pathway. Inhibition of PI3K-AKT-mTORC1 pathway-mediated glycolysis is conducive to the enhancement of FAO. PTEN, AMPK, PP2A, HIF2α, and FOXP3 are inhibitory molecules of the PI3K-AKT-mTORC1 pathway, which attenuate glycolysis. Oleic acids, increased reactive oxygen species levels, and PD1/CTLA-4 signal transduction are beneficial to the expression of FOXP3, inhibit glycolysis, and promote FAO. FAS is essential for the expression of immunosuppressive molecules. Here, a large amount of acetyl-coa produced by glycolysis can be used as a substrate for the synthesis of fatty acids and cholesterol, where mTORC1 has been reported to upregulate expression of CTLA-4, ICOS by activating the mevalonate pathway. Activation of the mevalonate pathway is also associated with enhanced PD-1 expression

Fig. 3

Lipid metabolism reprogramming promotes Tregs adaptation in TME. In the tumor microenvironment, most of the glucose and oxygen transported by disordered vessels are taken up by tumor cells, resulting in a hypoxia and glucose deprivation microenvironment, and the production of large amounts of lactate is detrimental to immune cell survival. Tumor-associated adipocytes are activated and promote lipid accumulation. Tregs highly express membrane receptor CD36 to uptake lipids and activate the PPAR-β pathway to enhance lipid utilization. Foxp3 expression also promotes lipid oxidation and interacts with Myc to regulate lactate dehydrogenase reaction direction, resisting the harmful effects of lactic acid accumulation. LKB1 prevents STAT4 activation-dependent CNS2 methylation of Foxp3, thereby preventing its destabilization. LKB1 also activates AMPK to inhibit mTORC1 pathway-mediated glycolysis. Under hypoxic conditions, activated HIF-1α enhances lipid metabolism and Fxop3 expression. CTLA-4 signaling activates PTEN to inhibit the mTOR pathway. Activation of the mevalonate pathway upregulates SREBP-mediated PD-1 expression, as well as RAS-STAT5-dependent Foxp3 expression

Fig. 4

Lipid accumulation amplifies Treg suppression function. CD36 is up-regulated in both Teffs and Tregs, and the uptake of oxidized low-density lipoprotein (OxLDL) by CD36 leads to lipid peroxidation-mediated mitochondrial destruction, which interferes with metabolism and promotes cell senescence. Tregs effectively prevent lipid peroxidation by upregulating GPX4 and ensuring a high level of lipid metabolism. Apoptotic tumor cells promote mevalonate pathway-dependent cholesterol synthesis and CTLA-4 expression in Tregs by activating the PD1-PTEN signaling pathway. IDO receptor activation potentiates PD1-mediated PTEN activation. Lipids and SCFAs in TME promote the expression of Foxp3. Foxp3 promotes the expression of the PD1 gene by promoting the nuclear translocation of NFAT1. In addition, Foxp3 maintained the high level of cAMP and activated the mevalonate pathway through cAMP/PKA-SREBP1 to increase cholesterol level and CTLA-4 expression