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Metabolic profiles of regulatory T cells in the tumour microenvironment

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

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.

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Abbreviations

AHR:

Aryl hydrocarbon receptor

BCAA:

Branched-chain amino acids

ETC:

Electron transport chain

FAO:

Fatty acid oxidation

FAS:

Fatty acid synthesis

HIF:

Hypoxia-inducible factor

IDO:

Indoleamine 2, 3-dioxygenase

iTreg:

Induced Tregs

mTOR:

Mammalian target of rapamycin

nTregs:

Natural Tregs

OXPHOS:

Oxidative phosphorylation

RHOA:

Ras homolog family member A

ROS:

Reactive oxygen species

TCA:

Tri-carboxylic acid

Tconv:

Conventional T cells

TGF-β:

Transforming growth factor beta

TI-Tregs:

Tumour-infiltrating Tregs

TME:

Tumour microenvironment

Treg:

Regulatory T cells

WT:

Wild-type

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Authors and Affiliations

  1. Division of Molecular Oncology and Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, The Netherlands

    Disha Rao, Fabienne Verburg, Daniel S. Peeper, Ruben Lacroix & Christian U. Blank

  2. Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Christian U. Blank

  3. Department of Internal Medicine III, Hematology and Medical Oncology, University Hospital Regensburg, Regensburg, Germany

    Kathrin Renner

  4. Oncode Institute, Utrecht, The Netherlands

    Daniel S. Peeper

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  1. Disha Rao
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  2. Fabienne Verburg
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  3. Kathrin Renner
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  4. Daniel S. Peeper
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  5. Ruben Lacroix
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  6. Christian U. Blank
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Contributions

D.R, R.L and C.U.B conceptualised the idea for the manuscript. All authors contributed to the literature search. The first draft of the manuscript was written by D.R, F.V and R.L. All authors were involved in critical revision of the manuscript and approval of the final manuscript.

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Correspondence to Christian U. Blank.

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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.

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Ruben Lacroix and Christian U Blank: shared last authors.

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Rao, D., Verburg, F., Renner, K. et al. Metabolic profiles of regulatory T cells in the tumour microenvironment. Cancer Immunol Immunother 70, 2417–2427 (2021). https://doi.org/10.1007/s00262-021-02881-z

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