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Review
. 2021 Sep;70(9):2417-2427.
doi: 10.1007/s00262-021-02881-z. Epub 2021 Feb 12.

Metabolic profiles of regulatory T cells in the tumour microenvironment

Disha Rao  1 , Fabienne Verburg  1 , Kathrin Renner  2 , Daniel S Peeper  1   3 , Ruben Lacroix  1 , Christian U Blank  4   5
Affiliations
Review

Metabolic profiles of regulatory T cells in the tumour microenvironment

Disha Rao et al. Cancer Immunol Immunother. 2021 Sep.

Abstract

Metabolic reprogramming of cancer cells generates a tumour microenvironment (TME) characterised by nutrient restriction, hypoxia, acidity and oxidative stress. While these conditions are unfavourable for infiltrating effector T cells, accumulating evidence suggests that regulatory T cells (Tregs) continue to exert their immune-suppressive functions within the TME. The advantages of Tregs within the TME stem from their metabolic profile. Tregs rely on oxidative phosphorylation for their functions, which can be fuelled by a variety of substrates. Even though Tregs are an attractive target to augment anti-tumour immune responses, it remains a challenge to specifically target intra-tumoral Tregs. We provide a comprehensive review of distinct mechanistic links and pathways involved in regulation of Treg metabolism under the prevailing conditions within the tumour. We also describe how these Tregs differ from the ones in the periphery, and from conventional T cells in the tumour. Targeting pathways responsible for adaptation of Tregs in the tumour microenvironment improves anti-tumour immunity in preclinical models. This may provide alternative therapies aiming at reducing immune suppression in the tumour.

Keywords: Acidity; Hypoxia; Metabolism; Nutrient depletion; Oxidative stress; Treg.

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Conflict of interest statement

C.U.B declares the following potential COI: advisory roles for BMS, MSD, Roche, Novartis, GSK, AZ, Pfizer, Lilly, GenMab, Pierre Fabre, Third Rock Ventures, research funding from BMS, Novartis, NanoString, co-founder of Immagene B.V. D.S.P received research support from MSD and BMS and is co-founder, shareholder and advisor of Immagene B.V.

Figures

Fig. 1
Fig. 1
Tumour-infiltrating (TI) Tregs adapt to the metabolic stresses often experienced in the tumour microenvironment (TME). TI-Tregs increase their glucose uptake via glucose transporters (GLUT) converting it to pyruvate via glycolysis. The conversion of pyruvate to lactate seldom occurs in TI-Tregs. Pyruvate is instead converted to acetyl-CoA and metabolized in the mitochondria to fuel the tri-carboxylic acid (TCA) cycle. The intermediates of TCA cycle can also be utilized for fatty acid synthesis (FAS) by TI-Tregs. Alternatively, TI-Tregs can take up free fatty acids (FA) from the TME via fatty acid transporters (e.g. CD36). This process is aided by the presence of fatty acid-binding proteins (FABP). FA is then converted to fatty acyl CoA to further be oxidized in the mitochondria, termed fatty acid oxidation (FAO). In addition, the TCA cycle can also be fuelled by the derivatives of amino acid metabolism. For example, glutamate produced from glutamine is converted to α-ketoglutarate which enters the TCA cycle. Furthermore, TI-Tregs have increased expression of metabotropic glutamate receptor 1 (mGluR1), which allows the uptake of glutamate from the TME. The reducing equivalents NADH and FADH2 are synthesized during the TCA cycle which in turn transfers electrons to the electron transport chain (ETC). The direction of electron transfer across the ETC complexes is depicted by dashed lines. The membrane potential created by the ETC drives phosphorylation of ADP to ATP in the presence of oxygen (OXPHOS). The reactive oxygen species (ROS) produced due to increased OXPHOS is scavenged by glutathione thereby protecting TI-Tregs from oxidative stress. Inhibitors that are shown to alter TI-Treg metabolism and their targets are depicted in red
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References

    1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646–674. doi: 10.1016/j.cell.2011.02.013. - DOI - PubMed
    1. Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519–530. doi: 10.1085/jgp.8.6.519. - DOI - PMC - PubMed
    1. Weinberg F, Hamanaka R, Wheaton WW, et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc Natl Acad Sci USA. 2010;107:8788–8793. doi: 10.1073/pnas.1003428107. - DOI - PMC - PubMed
    1. Yang LV. Tumor microenvironment and metabolism. Int J Mol Sci. 2017;18:278. doi: 10.3390/ijms18122729. - DOI - PMC - PubMed
    1. Semenza GL. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene. 2010;29:625–634. doi: 10.1038/onc.2009.441. - DOI - PMC - PubMed

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