Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth

Abstract

The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.

Treg programming and therapeutic reprogramming in cancer

“…This switch is directed by CD28 co‐stimulation, which activates PI3K/AKT, inducing the expression of the glucose transporter Glut1, and increasing glucose uptake for glycolysis . However, Tregs exhibit a much less distinctive switch to glycolysis upon activation and instead utilize a more diverse set of energy‐generating pathways, including fatty acid oxidation (FAO) and glutaminolysis to support their preference for the OXPHOS pathway . The importance of OXPHOS in Tregs is clear, as deletion of two important OXPHOS regulators, peroxisome proliferator‐activated receptor γ co‐activator 1a ( Pgc1a ) or sirtuin (Sirt) 3, impairs Tregs suppressive function both in vitro and in vivo …”

“…In the context of low glucose and high lactate, which is typical of most TMEs, Foxp3 expression in Tregs can increase OXPHOS, impede glycolysis by repressing the expression of Myc (a major transcriptional activator of glycolytic genes), and increase resistance to high concentrations of lactate . In multiple murine tumour models, TI‐Tregs have proven to be less vulnerable to glucose restriction than other effector T‐cells . However, in some settings, inhibition of glycolysis in TI‐Tregs reversed Treg suppressive function and promoted anti‐tumour immunity .…”

Regulation of regulatory T cells in cancer

“…Co‐stimulatory ligands, cytokines and chemokines are well‐established contributors to tTreg cell preferential expansion/maintenance in the tumour microenvironment, but recent evidence points also towards a peculiar cell‐intrinsic metabolism as a means by which tTreg cells survive, expand and exert their function within tumours . Importantly, tumour‐infiltrating tTreg cells display high expression of the glucose transporter Glut1 compared with splenic Treg cells, and are capable of increased glucose uptake in mouse tumour models . Such an improved glucose usage may in turn fuel fatty acid biosynthesis, in line with observations of a tTreg high neutral lipid content .…”

Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review

“…As indicated in open literature sources, the advantage of Tregs over conventional T cells (Tconvs) in TME may be dependent on the capacity of Tregs cells to compete for glucose and perform FAS and FAO at the higher rates than those of Tconvs. Additionally, it is proposed that FAS, rather than FA uptake, shapes the lipid Treg pool and contributes to Treg proliferation, after considering the high neutral lipid content and the metabolite signature observed in tumour bed Tregs …”

“…Recent studies have established that metabolic restrains, such as glucose restriction, impair the activities of effector T cells in TME. 69,83 In the same context, the remarkable expansion of acti- FAs content plays a crucial part in the levels of FAO and oxidative phosphorylation in cells, among which the former is a keyway for immunocytes to produce ATP. 87,88 Lipids are known to be the essential materials for cells, and their depletion in CD8 + T cells dramatically inhibits cell proliferation and signal transduction, which partly explains the lower number of CD8 + T cells in HCC than in adjacent tissues.…”