Progress in metabolism of the immune cells in tumor microenvironment

doi:10.3969/j.issn.1674-8115.2022.08.018

Abstract

Abstract:

Metabolic reprogramming refers to cells' mechanism to change their metabolic patterns in order to meet the increased energy demand caused by growth and proliferation. By way of metabolic reprogramming such as the Warburg effect, tumor cells gain rich energy to support their own survival, growth, and metastasis. The tumor microenvironment (TME) is the internal environment in which tumor cells survive, containing not only tumor cells, but also stromal cells, immune cells, and other components that are closely related to tumor cells. Meanwhile, tumor cells regulate intercellular function and signaling via secreting cytokines, metabolites, and other molecules and shape a commonly hypoxic, acidic, and nutrient-deprived TME which contributes the most to immune resistance. However, rapidly proliferating tumor cells compete for relatively scarce nutrients with immune cells, consequently, producing an immunosuppressive metabolism microenvironment. Under the influence of immunosuppressive TME, immune cells generate tolerance phenotype-related metabolic adaptations through metabolic reprogramming to satisfy their own needs and further perform anti-tumor or immunosuppressive roles. The response of immune cells to tumor cells mainly depends on respective unique metabolic pathways, which are related to the type and function of immune cells. Moreover, the functional properties of immune cells are directly associated with the immunotherapy effects. Regulating metabolic pathways of immune cells provides a great direction for cancer therapy. In this paper, the main metabolic pathways of immune cells in TME is described, the relationship between their metabolic characteristics and immune functions is summarized, and the mechanism of metabolic pathways underlying the functions of immune cells is further discussed, providing new insights for unveiling tumor immunosuppressive microenvironment and improving the efficacy of tumor immunotherapy.

Key words: tumor microenvironment (TME), immune cell, metabolic pathway, immunity function

CLC Number:

R772.2

LIN Jiayu, QIN Jiejie, JIANG Lingxi. Progress in metabolism of the immune cells in tumor microenvironment[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1122-1130.

Figures/Tables 2

TrendMD

References 66

1	DEBERARDINIS R J, LUM J J, HATZIVASSILIOU G, et al. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation[J]. Cell Metab, 2008, 7(1): 11-20.
2	GUERRA L, BONETTI L, BRENNER D. Metabolic modulation of immunity: a new concept in cancer immunotherapy[J]. Cell Rep, 2020, 32(1): 107848.
3	DOMBLIDES C, LARTIGUE L, FAUSTIN B. Control of the antitumor immune response by cancer metabolism[J]. Cells, 2019, 8(2): 104.
4	BISWAS S K. Metabolic reprogramming of immune cells in cancer progression[J]. Immunity, 2015, 43(3): 435-449.
5	FAUBERT B, SOLMONSON A, DEBERARDINIS R J. Metabolic reprogramming and cancer progression[J]. Science, 2020, 368(6487): eaaw5473.
6	LEONE R D, POWELL J D. Metabolism of immune cells in cancer[J]. Nat Rev Cancer, 2020, 20(9): 516-531.
7	WARD P S, THOMPSON C B. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate[J]. Cancer Cell, 2012, 21(3): 297-308.
8	CHANG C H, QIU J, O'SULLIVAN D, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression[J]. Cell, 2015, 162(6): 1229-1241.
9	BISWAS S K, ALLAVENA P, MANTOVANI A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions[J]. Semin Immunopathol, 2013, 35(5): 585-600.
10	MANTOVANI A, ALLAVENA P. The interaction of anticancer therapies with tumor-associated macrophages[J]. J Exp Med, 2015, 212(4): 435-445.
11	MANTOVANI A, MARCHESI F, MALESCI A, et al. Tumour-associated macrophages as treatment targets in oncology[J]. Nat Rev Clin Oncol, 2017, 14(7): 399-416.
12	DAI X M, LU L S, DENG S K, et al. USP7 targeting modulates anti-tumor immune response by reprogramming tumor-associated macrophages in lung cancer[J]. Theranostics, 2020, 10(20): 9332-9347.
13	QING J N, ZHANG Z Z, NOVÁK P, et al. Mitochondrial metabolism in regulating macrophage polarization: an emerging regulator of metabolic inflammatory diseases[J]. Acta Biochim Biophys Sin (Shanghai), 2020, 52(9): 917-926.
14	MOON J S, HISATA S, PARK M A, et al. mTORC1-induced HK1-dependent glycolysis regulates NLRP3 inflammasome activation[J]. Cell Rep, 2015, 12(1): 102-115.
15	HASCHEMI A, KOSMA P, GILLE L, et al. The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism[J]. Cell Metab, 2012, 15(6): 813-826.
16	VATS D, MUKUNDAN L, ODEGAARD J I, et al. Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation[J]. Cell Metab, 2006, 4(1): 13-24.
17	SU P, WANG Q, BI E G, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages[J]. Cancer Res, 2020, 80(7): 1438-1450.
18	BANTUG G R, GALLUZZI L, KROEMER G, et al. The spectrum of T cell metabolism in health and disease[J]. Nat Rev Immunol, 2018, 18(1): 19-34.
19	RUFFELL B, COUSSENS L M. Macrophages and therapeutic resistance in cancer[J]. Cancer Cell, 2015, 27(4): 462-472.
20	RODRÍGUEZ-ESPINOSA O, ROJAS-ESPINOSA O, MORENO-ALTAMIRANO M M B, et al. Metabolic requirements for neutrophil extracellular traps formation[J]. Immunology, 2015, 145(2): 213-224.
21	ANCEY P B, CONTAT C, BOIVIN G, et al. GLUT1 expression in tumor-associated neutrophils promotes lung cancer growth and resistance to radiotherapy[J]. Cancer Res, 2021, 81(9): 2345-2357.
22	RICE C M, DAVIES L C, SUBLESKI J J, et al. Tumour-elicited neutrophils engage mitochondrial metabolism to circumvent nutrient limitations and maintain immune suppression[J]. Nat Commun, 2018, 9(1): 5099.
23	ISAACSON B, MANDELBOIM O. Sweet killers: NK cells need glycolysis to kill tumors[J]. Cell Metab, 2018, 28(2): 183-184.
24	LOFTUS R M, ASSMANN N, KEDIA-MEHTA N, et al. Amino acid-dependent cMyc expression is essential for NK cell metabolic and functional responses in mice[J]. Nat Commun, 2018, 9(1): 2341.
25	HARMON C, ROBINSON M W, HAND F, et al. Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis[J]. Cancer Immunol Res, 2019, 7(2): 335-346.
26	MICHELET X, DYCK L, HOGAN A, et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses[J]. Nat Immunol, 2018, 19(12): 1330-1340.
27	KRAWCZYK C M, HOLOWKA T, SUN J, et al. Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation[J]. Blood, 2010, 115(23): 4742-4749.
28	EVERTS B, AMIEL E, HUANG S C C, et al. TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKɛ supports the anabolic demands of dendritic cell activation[J]. Nat Immunol, 2014, 15(4): 323-332.
29	HERBER D L, CAO W, NEFEDOVA Y, et al. Lipid accumulation and dendritic cell dysfunction in cancer[J]. Nat Med, 2010, 16(8): 880-886.
30	CUBILLOS-RUIZ J R, SILBERMAN P C, RUTKOWSKI M R, et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis[J]. Cell, 2015, 161(7): 1527-1538.
31	HOSSAIN F, AL-KHAMI A A, WYCZECHOWSKA D, et al. Inhibition of fatty acid oxidation modulates immunosuppressive functions of myeloid-derived suppressor cells and enhances cancer therapies[J]. Cancer Immunol Res, 2015, 3(11): 1236-1247.
32	DIAS A S, ALMEIDA C R, HELGUERO L A, et al. Metabolic crosstalk in the breast cancer microenvironment[J]. Eur J Cancer, 2019, 121: 154-171.
33	AL-KHAMI A A, ZHENG L Q, DEL VALLE L, et al. Exogenous lipid uptake induces metabolic and functional reprogramming of tumor-associated myeloid-derived suppressor cells[J]. Oncoimmunology, 2017, 6(10): e1344804.
34	MICHALEK R D, GERRIETS V A, JACOBS S R, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4⁺ T cell subsets[J]. J Immunol, 2011, 186(6): 3299-3303.
35	SHARMA P, HU-LIESKOVAN S, WARGO J A, et al. Primary, adaptive, and acquired resistance to cancer immunotherapy[J]. Cell, 2017, 168(4): 707-723.
36	GELTINK R, KYLE R L, PEARCE E L. Unraveling the complex interplay between T cell metabolism and function[J]. Annu Rev Immunol, 2018, 36: 461-488.
37	WAICKMAN A T, POWELL J D. mTOR, metabolism, and the regulation of T-cell differentiation and function[J]. Immunol Rev, 2012, 249(1): 43-58.
38	FRAUWIRTH K A, RILEY J L, HARRIS M H, et al. The CD28 signaling pathway regulates glucose metabolism[J]. Immunity, 2002, 16(6): 769-777.
39	HO P C, BIHUNIAK J D, MACINTYRE A N, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses[J]. Cell, 2015, 162(6): 1217-1228.
40	DE ROSA V, GALGANI M, PORCELLINI A, et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants[J]. Nat Immunol, 2015, 16(11): 1174-1184.
41	HAAS R, SMITH J, ROCHER-ROS V, et al. Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions[J]. PLoS Biol, 2015, 13(7): e1002202.
42	KUMAGAI S, KOYAMA S, ITAHASHI K, et al. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments[J]. Cancer Cell, 2022, 40(2): 201-218.e9.
43	WATSON M J, VIGNALI P D A, MULLETT S J, et al. Metabolic support of tumour-infiltrating regulatory T cells by lactic acid[J]. Nature, 2021, 591(7851): 645-651.
44	KIDANI Y, ELSAESSER H, HOCK M B, et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity[J]. Nat Immunol, 2013, 14(5): 489-499.
45	YANG W, BAI Y B, XIONG Y, et al. Potentiating the antitumour response of CD8⁺ T cells by modulating cholesterol metabolism[J]. Nature, 2016, 531(7596): 651-655.
46	WANG H P, FRANCO F, TSUI Y C, et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors[J]. Nat Immunol, 2020, 21(3): 298-308.
47	ZENG H, YANG K, CLOER C, et al. mTORC1 couples immune signals and metabolic programming to establish Treg cell function[J]. Nature, 2013, 499(7459): 485-490.
48	TAKE Y, KOIZUMI S, NAGAHISA A. Prostaglandin E receptor 4 antagonist in cancer immunotherapy: mechanisms of action[J]. Front Immunol, 2020, 11: 324.
49	MUNN D H, SHARMA M D, BABAN B, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2, 3-dioxygenase[J]. Immunity, 2005, 22(5): 633-642.
50	GEIGER R, RIECKMANN J C, WOLF T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity[J]. Cell, 2016, 167(3): 829-842.e13.
51	BIAN YJ, LI W, KREMER D M, et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation[J]. Nature, 2020, 585(7824): 277-282.
52	MOLLER S H, HSUEH P C, YU Y R, et al. Metabolic programs tailor T cell immunity in viral infection, cancer, and aging [J]. Cell Metab, 2022, 34(3): 378-395.
53	LIU Y N, YANG J F, HUANG D J, et al. Hypoxia induces mitochondrial defect that promotes T cell exhaustion in tumor microenvironment through MYC-regulated pathways[J]. Front Immunol, 2020, 11: 1906.
54	HE J L, SHANGGUAN X, ZHOU W, et al. Glucose limitation activates AMPK coupled SENP1-Sirt3 signalling in mitochondria for T cell memory development[J]. Nat Commun, 2021, 12(1): 4371.
55	SCHARPING N E, MENK A V, MORECI R S, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction[J]. Immunity, 2016, 45(2): 374-388.
56	KURAI J, CHIKUMI H, HASHIMOTO K, et al. Antibody-dependent cellular cytotoxicity mediated by cetuximab against lung cancer cell lines[J]. Clin Cancer Res, 2007, 13(5): 1552-1561.
57	PITZALIS C, JONES G W, BOMBARDIERI M, et al. Ectopic lymphoid-like structures in infection, cancer and autoimmunity[J]. Nat Rev Immunol, 2014, 14(7): 447-462.
58	CASSIM S, POUYSSEGUR J. Tumor microenvironment: a metabolic player that shapes the immune response[J]. Int J Mol Sci, 2019, 21(1): 157.
59	WATERS L R, AHSAN F M, WOLF D M, et al. Initial B cell activation induces metabolic reprogramming and mitochondrial remodeling[J]. iScience, 2018, 5: 99-109.
60	BROWN T P, GANAPATHY V. Lactate/GPR81 signaling and proton motive force in cancer: role in angiogenesis, immune escape, nutrition, and Warburg phenomenon[J]. Pharmacol Ther, 2020, 206: 107451.
61	KOUIDHI S, BEN AYED F, BENAMMAR ELGAAIED A. Targeting tumor metabolism: a new challenge to improve immunotherapy[J]. Front Immunol, 2018, 9: 353.
62	HALFORD S E R, JONES P, WEDGE S, et al. A first-in-human first-in-class (FIC) trial of the monocarboxylate transporter 1 (MCT1) inhibitor AZD3965 in patients with advanced solid tumours[J]. J Clin Oncol, 2017, 35(15_suppl): 2516.
63	OH M H, SUN I H, ZHAO L, et al. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells[J]. J Clin Invest, 2020, 130(7): 3865-3884.
64	LEONE R D, ZHAO L, ENGLERT J M, et al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion[J]. Science, 2019, 366(6468): 1013-1021.
65	VOSS K, LUTHERS C R, POHIDA K, et al. Fatty acid synthase contributes to restimulation-induced cell death of human CD4 T cells[J]. Front Mol Biosci, 2019, 6: 106.
66	FALCHOOK G, INFANTE J, ARKENAU H T, et al. First-in-human study of the safety, pharmacokinetics, and pharmacodynamics of first-in-class fatty acid synthase inhibitor TVB-2640 alone and with a taxane in advanced tumors[J]. EClinicalMedicine, 2021, 34: 100797.

Immunity type	Cell type	Metabolic pathway	Reference
Innate immunity
	M1-type TAMs	PPP	［12-13］
	M2-type TAMs	OXPHOS， FAO	［16-17］
	TANs	Glycolysis	［20］
	NKs	Glycolysis， OXPHOS	［23］
	DCs	Glycolysis	［27］
	MDSCs	Glycolysis， OXPHOS	［31］
Adaptive immunity
	Effector T cells	Glycolysis， lipid metabolism	［37，44］
	Tregs	Lipid metabolism， OXPHOS	［34］
	Effector B cells	Glycolysis， OXPHOS	［58-59］

Immunity type	Cell type	Metabolic pathway	Reference
Innate immunity
	M1-type TAMs	PPP	［12-13］
	M2-type TAMs	OXPHOS， FAO	［16-17］
	TANs	Glycolysis	［20］
	NKs	Glycolysis， OXPHOS	［23］
	DCs	Glycolysis	［27］
	MDSCs	Glycolysis， OXPHOS	［31］
Adaptive immunity
	Effector T cells	Glycolysis， lipid metabolism	［37，44］
	Tregs	Lipid metabolism， OXPHOS	［34］
	Effector B cells	Glycolysis， OXPHOS	［58-59］

[1]	WANG Yuxin, SUN Ruiqi, LIU Jianhua, HE Weina. Development of pH-responsive fluorescent probe for tumor microenvironment imaging [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 875-884.
[2]	Jing-wei LI, Li-wen WANG, Ling-xi JIANG, Qian ZHAN, Hao CHEN, Bai-yong SHEN. Review of immunosuppressive tumor microenvironment of pancreatic cancer [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1103-1108.
[3]	ZHOU Han, YANG Xiao-sheng, LIAO Chen-long, ZHANG Wen-chuan. Analysis on characteristics of diabetic foot ulceration-related genes and immune cells [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2020, 40(10): 1354-1359.
[4]	PING Feng, GUO Yong, LIU Yu-jing, CAO Yong-mei, LI Ying-chuan. Application of metabonomics in the diagnosis and treatment of acute kidney injury#br# [J]. , 2017, 37(8): 1174-.