Metabolites in the Tumor Microenvironment Reprogram Functions of Immune Effector Cells Through Epigenetic Modifications

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2021 Apr 30

PMID 33927716

Citations 9

Authors

Yijia Li

Yangzhe Wu

Yi Hu

Affiliations

Soon will be listed here.

Abstract

Cellular metabolism of both cancer and immune cells in the acidic, hypoxic, and nutrient-depleted tumor microenvironment (TME) has attracted increasing attention in recent years. Accumulating evidence has shown that cancer cells in TME could outcompete immune cells for nutrients and at the same time, producing inhibitory products that suppress immune effector cell functions. Recent progress revealed that metabolites in the TME could dysregulate gene expression patterns in the differentiation, proliferation, and activation of immune effector cells by interfering with the epigenetic programs and signal transduction networks. Nevertheless, encouraging studies indicated that metabolic plasticity and heterogeneity between cancer and immune effector cells could provide us the opportunity to discover and target the metabolic vulnerabilities of cancer cells while potentiating the anti-tumor functions of immune effector cells. In this review, we will discuss the metabolic impacts on the immune effector cells in TME and explore the therapeutic opportunities for metabolically enhanced immunotherapy.

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References

Ali A, Makings J, Ley K . Regulatory T Cell Stability and Plasticity in Atherosclerosis. Cells. 2020; 9(12). PMC: 7764358. DOI: 10.3390/cells9122665. View

Henderson T, Ness K, Cohen H . Accelerated aging among cancer survivors: from pediatrics to geriatrics. Am Soc Clin Oncol Educ Book. 2014; :e423-30. DOI: 10.14694/EdBook_AM.2014.34.e423. View

Hyun K, Jeon J, Park K, Kim J . Writing, erasing and reading histone lysine methylations. Exp Mol Med. 2017; 49(4):e324. PMC: 6130214. DOI: 10.1038/emm.2017.11. View

Warburg O, Wind F, Negelein E . THE METABOLISM OF TUMORS IN THE BODY. J Gen Physiol. 2009; 8(6):519-30. PMC: 2140820. DOI: 10.1085/jgp.8.6.519. View

Verdone L, Agricola E, Caserta M, Di Mauro E . Histone acetylation in gene regulation. Brief Funct Genomic Proteomic. 2006; 5(3):209-21. DOI: 10.1093/bfgp/ell028. View

Chang C, Qiu J, OSullivan D, Buck M, Noguchi T, Curtis J . Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression. Cell. 2015; 162(6):1229-41. PMC: 4864363. DOI: 10.1016/j.cell.2015.08.016. View

Keith B, Simon M . Hypoxia-inducible factors, stem cells, and cancer. Cell. 2007; 129(3):465-72. PMC: 3150586. DOI: 10.1016/j.cell.2007.04.019. View

Geiger R, Rieckmann J, Wolf T, Basso C, Feng Y, Fuhrer T . L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell. 2016; 167(3):829-842.e13. PMC: 5075284. DOI: 10.1016/j.cell.2016.09.031. View

Lequeux A, Noman M, Xiao M, Sauvage D, Van Moer K, Viry E . Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints. Cancer Lett. 2019; 458:13-20. DOI: 10.1016/j.canlet.2019.05.021. View

10.

Aspeslagh S, Morel D, Soria J, Postel-Vinay S . Epigenetic modifiers as new immunomodulatory therapies in solid tumours. Ann Oncol. 2018; 29(4):812-824. DOI: 10.1093/annonc/mdy050. View

11.

Watson M, Vignali P, Mullett S, Overacre-Delgoffe A, Peralta R, Grebinoski S . Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature. 2021; 591(7851):645-651. PMC: 7990682. DOI: 10.1038/s41586-020-03045-2. View

12.

Zhou Z, Chen H, Xie R, Wang H, Li S, Xu Q . Epigenetically modulated FOXM1 suppresses dendritic cell maturation in pancreatic cancer and colon cancer. Mol Oncol. 2019; 13(4):873-893. PMC: 6441919. DOI: 10.1002/1878-0261.12443. View

13.

Li Y, Patel S, Roszik J, Qin Y . Hypoxia-Driven Immunosuppressive Metabolites in the Tumor Microenvironment: New Approaches for Combinational Immunotherapy. Front Immunol. 2018; 9:1591. PMC: 6054965. DOI: 10.3389/fimmu.2018.01591. View

14.

Xu Y, Xiang Z, Alnaggar M, Kouakanou L, Li J, He J . Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer. Cell Mol Immunol. 2020; 18(2):427-439. PMC: 8027668. DOI: 10.1038/s41423-020-0515-7. View

15.

Cho S, Raybuck A, Blagih J, Kemboi E, Haase V, Jones R . Hypoxia-inducible factors in CD4 T cells promote metabolism, switch cytokine secretion, and T cell help in humoral immunity. Proc Natl Acad Sci U S A. 2019; 116(18):8975-8984. PMC: 6500120. DOI: 10.1073/pnas.1811702116. View

16.

Xu Y, Chaudhury A, Zhang M, Savoldo B, Metelitsa L, Rodgers J . Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J Clin Invest. 2016; 126(7):2678-88. PMC: 4922684. DOI: 10.1172/JCI85834. View

17.

Hsu C, Shi J, Yuan C, Zhao D, Jiang S, Lyu J . Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer. Genes Dev. 2018; 32(1):58-69. PMC: 5828395. DOI: 10.1101/gad.303784.117. View

18.

Black J, Van Rechem C, Whetstine J . Histone lysine methylation dynamics: establishment, regulation, and biological impact. Mol Cell. 2012; 48(4):491-507. PMC: 3861058. DOI: 10.1016/j.molcel.2012.11.006. View

19.

Schmolka N, Serre K, Grosso A, Rei M, Pennington D, Gomes A . Epigenetic and transcriptional signatures of stable versus plastic differentiation of proinflammatory γδ T cell subsets. Nat Immunol. 2013; 14(10):1093-1100. PMC: 4834994. DOI: 10.1038/ni.2702. View

20.

Ganesan A, Arimondo P, Rots M, Jeronimo C, Berdasco M . The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenetics. 2019; 11(1):174. PMC: 6888921. DOI: 10.1186/s13148-019-0776-0. View