Lipid metabolism in tumor-infiltrating T cells: mechanisms and applications

Abstract

As an essential part of adaptive immunity, T cells coordinate the immune responses against pathogens and cancer cells. Lipid metabolism has emerged as a key regulator for the activation, differentiation, and effector functions of T cells. Therefore, uncovering the molecular mechanisms by which lipid metabolism dictates T cell biology is of vital importance. The tumor microenvironment is a hostile milieu, i.e. often characterized by nutrient restriction. In this environment, various cells, such as T cells and cancer cells, reprogram their metabolism, including their lipid metabolism, to meet their energy and functional needs. Here, we review the participation of fatty acid and cholesterol metabolism homeostasis in orchestrating T cell biology. We demonstrate how the tumor microenvironment reshapes the lipid metabolism in T cells. Importantly, we highlight the current cancer therapeutic interventions that target fatty acid and cholesterol metabolism of T cells. By offering a holistic understanding of how lipid metabolic adaption by T cells facilitates their immunosurveillance in the tumor microenvironment, we believe this review and the future studies might inspire the next-generation immunotherapies.

Keywords

T cells / lipid metabolism / fatty acid metabolism / cholesterol metabolism / tumor microenvironment / cancer immunotherapies

References

[1] Ruterbusch M , Pruner KB , Shehata L et al. In vivo CD4⁺ T cell differentiation and function: revisiting the Th1/Th2 paradigm Annu Rev Immunol 2020; 38: 705- 25.

[2] Fox CJ , Hammerman PS , Thompson CB . Fuel feeds function: energy metabolism and the T-cell response Nat Rev Immunol 2005; 5: 844- 52.

[3] Yu W , Lei Q , Yang L et al. Contradictory roles of lipid metabolism in immune response within the tumor microenvironment J Hematol Oncol 2021; 14: 187.

[4] Bantug GR , Galluzzi L , Kroemer G et al. The spectrum of T cell metabolism in health and disease Nat Rev Immunol 2018; 18: 19- 34.

[5] O’Sullivan D , van der Windt GJW , Huang SC et al. Memory CD8⁺ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development Immunity 2014; 41: 75- 88.

[6] Berod L , Friedrich C , Nandan A et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells Nat Med 2014; 20: 1327- 33.

[7] Snaebjornsson MT , Janaki-Raman S , Schulze A . Greasing the wheels of the cancer machine: the role of lipid metabolism in cancer Cell Metab 2020; 31: 62- 76.

[8] Luo X , Zhao X , Cheng C et al. The implications of signaling lipids in cancer metastasis Exp Mol Med 2018; 50: 1- 10.

[9] Bian X , Liu R , Meng Y et al. Lipid metabolism and cancer J Exp Med 2021; 218: e20201606.

[10] Nakajima T , Kanno T , Yokoyama A et al. ACC1-expressing pathogenic T helper 2 cell populations facilitate lung and skin inflammation in mice J Exp Med 2021; 218: e20210639.

[11] Ricciardi S , Manfrini N , Alfieri R et al. The translational machinery of human CD4⁺ T cells is poised for activation and controls the switch from quiescence to metabolic remodeling Cell Metab 2018; 28: 895- 906.e5.

[12] Mamareli P , Kruse F , Lu C-W et al. Targeting cellular fatty acid synthesis limits T helper and innate lymphoid cell function during intestinal inflammation and infection Mucosal Immunol 2021; 14: 164- 76.

[13] Endo Y , Asou HK , Matsugae N et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1 Cell Rep 2015; 12: 1042- 55.

[14] Lee J , Walsh MC , Hoehn KL et al. Regulator of fatty acid metaoblism, acetyl CoA carboxylase 1 (ACC1), controls T cell immunity. J Immunol 2015; 192: 3190- 9.

[15] Young KE , Flaherty S , Woodman KM et al. Fatty acid synthase regulates the pathogenicity of Th17 cells J Leukoc Biol 2017; 102: 1229- 35.

[16] Lim SA , Wei J , Nguyen TM et al. Lipid signalling enforces functional specialization of Treg cells in tumours Nature 2021; 591: 306- 11.

[17] Su X , Abumrad NA . Cellular fatty acid uptake: a pathway under construction Trends Endocrinol Metab 2009; 20: 72- 7.

[18] Anderson CM , Stahl A . SLC27 fatty acid transport proteins Mol Aspects Med 2013; 34: 516- 28.

[19] Furuhashi M , Hotamisligil GS . Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets Nat Rev Drug Discovery 2008; 7: 489- 503.

[20] Angela M , Endo Y , Asou HK et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells Nat Commun 2016; 7: 13683.

[21] Field CS , Baixauli F , Kyle RL et al. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function Cell Metab 2020; 31: 422- 437.e5.

[22] Frizzell H , Fonseca R , Christo SN et al. Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes Sci Immunol 2020; 5: eaay9283.

[23] Houten SM , Wanders RJ . A general introduction to the biochemistry of mitochondrial fatty acid β-oxidation J Inherit Metab Dis 2010; 33: 469- 77.

[24] Frauwirth KA , Thompson CB . Regulation of T lymphocyte metabolism J Immunol 2004; 172: 4661- 5.

[25] Michalek RD , Gerriets VA , Jacobs SR et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4⁺ T cell subsets J Immunol 2011; 186: 3299- 303.

[26] Gerriets VA , Kishton RJ , Nichols AG et al. Metabolic programming and PDHK1 control CD4⁺ T cell subsets and inflammation J Clin Invest 2015; 125: 194- 207.

[27] Howie D , Cobbold SP , Adams E et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity JCI Insight 2017; 2: e89160.

[28] Angelin A , Gil-de-Gómez L , Dahiya S et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments Cell Metab 2017; 25: 1282- 93.e7.

[29] Pan Y , Kupper TS . Metabolic reprogramming and longevity of tissue-resident memory T cells Front Immunol 2018; 9: 1347.

[30] Cui G , Staron MM , Gray SM et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8⁺ T cell longevity Cell 2015; 161: 750- 61.

[31] Pearce EL , Walsh MC , Cejas PJ et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism Nature 2009; 460: 103- 7.

[32] van der Windt GJ , Everts B , Chang C-H et al. Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development Immunity 2012; 36: 68- 78.

[33] Patsoukis N , Bardhan K , Chatterjee P et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation Nat Commun 2015; 6: 6692.

[34] Raud B , Roy DG , Divakaruni AS et al. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation Cell Metab 2018; 28: 504- 15.e7.

[35] Ikonen E . Cellular cholesterol trafficking and compartmentalization Nat Rev Mol Cell Biol 2008; 9: 125- 38.

[36] Luo J , Yang H , Song B-L . Mechanisms and regulation of cholesterol homeostasis Nat Rev Mol Cell Biol 2020; 21: 225- 45.

[37] Goldstein JL , DeBose-Boyd RA , Brown MS . Protein sensors for membrane sterols Cell 2006; 124: 35- 46.

[38] Tontonoz P , Mangelsdorf DJ . Liver X receptor signaling pathways in cardiovascular disease Mol Endocrinol 2003; 17: 985- 93.

[39] Proto JD , Doran AC , Subramanian M et al. Hypercholesterolemia induces T cell expansion in humanized immune mice J Clin Invest 2018; 128: 2370- 5.

[40] Huang B , Song BL , Xu C . Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities Nat Metab 2020; 2: 132- 41.

[41] Kidani Y , Elsaesser H , Hock MB et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity Nat Immunol 2013; 14: 489- 99.

[42] Delgoffe GM , Pollizzi KN , Waickman AT et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2 Nat Immunol 2011; 12: 295- 303.

[43] Pollizzi KN , Sun I-H , Patel CH et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8⁺ T cell differentiation Nat Immunol 2016; 17: 704- 11.

[44] Delgoffe GM , Kole TP , Zheng Y et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment Immunity 2009; 30: 832- 44.

[45] Zeng H , Yang K , Cloer C et al. mTORC1 couples immune signals and metabolic programming to establish Treg-cell function Nature 2013; 499: 485- 90.

[46] Timilshina M , You Z , Lacher SM et al. Activation of mevalonate pathway via LKB1 is essential for stability of T(reg) cells Cell Rep 2019; 27: 2948- 61.e7.

[47] Johnson LA , Olsen RHJ , Merkens LS et al. Apolipoprotein E-low density lipoprotein receptor interaction affects spatial memory retention and brain ApoE levels in an isoform-dependent manner Neurobiol Dis 2014; 64: 150- 62.

[48] Bonacina F , Coe D , Wang G et al. Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation Nat Commun 2018; 9: 3083.

[49] Packard RR , Maganto-García E , Gotsman I et al. CD11c+ dendritic cells maintain antigen processing, presentation capabilities, and CD4+ T-cell priming efficacy under hypercholesterolemic conditions associated with atherosclerosis Circ Res 2008; 103: 965- 73.

[50] Maxwell KN , Fisher EA , Breslow JL . Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment Proc Natl Acad Sci USA 2005; 102: 2069- 74.

[51] Chang TY , Chang CCY , Ohgami N et al. Cholesterol sensing, trafficking, and esterification Annu Rev Cell Dev Biol 2006; 22: 129- 57.

[52] Bensinger SJ , Bradley MN , Joseph SB et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response Cell 2008; 134: 97- 111.

[53] Waddington KE , Robinson GA , Rubio-Cuesta B et al. LXR directly regulates glycosphingolipid synthesis and affects human CD4⁺ T cell function Proc Natl Acad Sci USA 2021; 118: e2017394118.

[54] Ito A , Hong C , Rong X et al. LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling Elife 2015; 4: e08009.

[55] Tavazoie MF , Pollack I , Tanqueco R et al. LXR/ApoE activation restricts innate immune suppression in cancer Cell 2018; 172: 825- 40.e18.

[56] Chang TY , Li B-L , Chang CCY et al. Acyl-coenzyme A:cholesterol acyltransferases Am J Physiol Endocrinol Metab 2009; 297: E1- 9.

[57] Yang W , Bai Y , Xiong Y et al. Potentiating the antitumour response of CD8⁺ T cells by modulating cholesterol metabolism Nature 2016; 531: 651- 5.

[58] Pearce EL , Poffenberger MC , Chang C-H et al. Fueling immunity: insights into metabolism and lymphocyte function Science 2013; 342: 1242454.

[59] Egeblad M , Nakasone ES , Werb Z . Tumors as organs: complex tissues that interface with the entire organism Dev Cell 2010; 18: 884- 901.

[60] Chang CH , Qiu J , O'Sullivan D et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression Cell 2015; 162: 1229- 41.

[61] Pacella I , Procaccini C , Focaccetti C et al. Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth Proc Natl Acad Sci USA 2018; 115: E6546- 55.

[62] Silverstein RL , Febbraio M . CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior Sci Signal 2009; 2: re3.

[63] Wang H , Franco F , Tsui Y-C et al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors Nat Immunol 2020; 21: 298- 308.

[64] Xu S , Chaudhary O , Rodríguez-Morales P et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8⁺ T cells in tumors Immunity 2021; 54: 1561- 77.e7.

[65] Ma X , Xiao L , Liu L et al. CD36-mediated ferroptosis dampens intratumoral CD8⁺ T cell effector function and impairs their antitumor ability Cell Metab 2021; 33: 1001- 12.e5.

[66] Lin R , Zhang H , Yuan Y et al. Fatty acid oxidation controls CD8⁺ tissue-resident memory T-cell survival in gastric adenocarcinoma Cancer Immunol Res 2020; 8: 479- 92.

[67] Kobayashi S , Wannakul T , Sekino K et al. Fatty acid-binding protein 5 limits the generation of Foxp3+ regulatory T cells through regulating plasmacytoid dendritic cell function in the tumor microenvironment Int J Cancer 2022; 150: 152- 63.

[68] Manzo T , Prentice BM , Anderson KG et al. Accumulation of long-chain fatty acids in the tumor microenvironment drives dysfunction in intrapancreatic CD8⁺ T cells J Exp Med 2020; 217: e20191920.

[69] Zhang Y , Kurupati R , Liu L et al. Enhancing CD8⁺ T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy Cancer Cell 2017; 32: 377- 91.e9.

[70] Zhang C , Yue C , Herrmann A et al. STAT3 activation-induced fatty acid oxidation in CD8⁺ T effector cells is critical for obesity-promoted breast tumor growth Cell Metab 2020; 31: 148- 61.e5.

[71] Ringel AE , Drijvers JM , Baker GJ et al. Obesity shapes metabolism in the tumor microenvironment to suppress anti-tumor immunity Cell 2020; 183: 1848- 66.e26.

[72] Pan Y , Tian T , Park CO et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism Nature 2017; 543: 252- 6.

[73] Paley MA , Kroy DC , Odorizzi PM et al. Progenitor and terminal subsets of CD8⁺ T cells cooperate to contain chronic viral infection Science 2012; 338: 1220- 5.

[74] Utzschneider DT , Charmoy M , Chennupati V et al. T cell factor 1-expressing memory-like CD8⁺ T cells sustain the immune response to chronic viral infections Immunity 2016; 45: 415- 27.

[75] Ogando J , Sáez ME , Santos J et al. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8⁺ T lymphocytes J ImmunoTher Cancer 2019; 7: 151.

[76] Chen W , Teo JMN , Yau SW et al. Chronic type I interferon signaling promotes lipid-peroxidation-driven terminal CD8⁺ T cell exhaustion and curtails anti-PD-1 efficacy Cell Rep 2022; 41: 111647.

[77] Bengsch B , Johnson AL , Kurachi M et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8⁺ T cell exhaustion Immunity 2016; 45: 358- 73.

[78] Vardhana SA , Hwee MA , Berisa M et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen Nat Immunol 2020; 21: 1022- 33.

[79] Scharping NE , Rivadeneira DB , Menk AV et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion Nat Immunol 2021; 22: 205- 15.

[80] Ma X , Bi E , Lu Y et al. Cholesterol induces CD8⁺ T cell exhaustion in the tumor microenvironment Cell Metab 2019; 30: 143- 56.e5.

[81] Lu Y , Hong B , Li H et al. Tumor-specific IL-9-producing CD8⁺ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers Proc Natl Acad Sci USA 2014; 111: 2265- 70.

[82] Ma X , Bi E , Huang C et al. Cholesterol negatively regulates IL-9-producing CD8⁺ T cell differentiation and antitumor activity J Exp Med 2018; 215: 1555- 69.

[83] Wu M , Zhang C , Li X-J et al. Anti-cancer effect of cap-translation inhibitor 4EGI-1 in human glioma U87 cells: involvement of mitochondrial dysfunction and ER stress Cell Physiol Biochem 2016; 40: 1013- 28.

[84] Kwon HJ , Lagace TA , McNutt MC et al. Molecular basis for LDL receptor recognition by PCSK9 Proc Natl Acad Sci USA 2008; 105: 1820- 5.

[85] Yuan J , Cai T , Zheng X et al. Potentiating CD8⁺ T cell antitumor activity by inhibiting PCSK9 to promote LDLR-mediated TCR recycling and signaling Protein Cell 2021; 12: 240- 60.

[86] Liu X , Bao X , Hu M et al. Inhibition of PCSK9 potentiates immune checkpoint therapy for cancer Nature 2020; 588: 693- 8.

[87] Sabatine MS , Giugliano RP , Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease N Engl J Med 2017; 376: 1713- 22.

[88] Baek AE , Yu YA , He S et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells Nat Commun 2017; 8: 864.

[89] Ma L , Wang L , Nelson AT et al. 27-Hydroxycholesterol acts on myeloid immune cells to induce T cell dysfunction, promoting breast cancer progression Cancer Lett 2020; 493: 266- 83.

[90] van der Windt GJ , O'Sullivan D , Everts B et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability Proc Natl Acad Sci USA 2013; 110: 14336- 41.

[91] Pawlak M , Lefebvre P , Staels B . Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease J Hepatol 2015; 62: 720- 33.

[92] Chowdhury PS , Chamoto K , Kumar A et al. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8⁺ T cells and facilitates anti-PD-1 therapy Cancer Immunol Res 2018; 6: 1375- 87.

[93] Chamoto K , Chowdhury PS , Kumar A et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity Proc Natl Acad Sci USA 2017; 114: E761- 70.

[94] Wan H , Xu B , Zhu N et al. PGC-1α activator-induced fatty acid oxidation in tumor-infiltrating CTLs enhances effects of PD-1 blockade therapy in lung cancer Tumori 2020; 106: 55- 63.

[95] Herrmann A , Priceman SJ , Swiderski P et al. CTLA4 aptamer delivers STAT3 siRNA to tumor-associated and malignant T cells J Clin Invest 2014; 124: 2977- 87.

[96] Pokhrel RH , Acharya S , Ahn J-H et al. AMPK promotes antitumor immunity by downregulating PD-1 in regulatory T cells via the HMGCR/p38 signaling pathway Mol Cancer 2021; 20: 133.

[97] Fu S , He K , Tian C et al. Impaired lipid biosynthesis hinders anti-tumor efficacy of intratumoral iNKT cells Nat Commun 2020; 11: 438.

[98] Xia Y , Xie Y , Yu Z et al. The mevalonate pathway is a druggable target for vaccine adjuvant discovery Cell 2018; 175: 1059- 73.e21.

[99] Lin C-Y , Gustafsson J-A . Targeting liver X receptors in cancer therapeutics Nat Rev Cancer 2015; 15: 216- 24.

[100] Carpenter KJ , Valfort A-C , Steinauer N et al. LXR-inverse agonism stimulates immune-mediated tumor destruction by enhancing CD8 T-cell activity in triple negative breast cancer Sci Rep 2019; 9: 19530.

[101] Lei J , Wang H , Zhu D et al. Combined effects of avasimibe immunotherapy, doxorubicin chemotherapy, and metal-organic frameworks nanoparticles on breast cancer J Cell Physiol 2020; 235: 4814- 23.

[102] Li M , Yang Y , Wei J et al. Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8⁺ T cells Nanomedicine 2018; 14: 2541- 50.

[103] Lee IK , Song H , Kim H et al. RORα regulates cholesterol metabolism of CD8⁺ T cells for anticancer immunity Cancers (Basel) 2020; 12: 1733.

[104] Chan JD , Lai J , Slaney CY et al. Cellular networks controlling T cell persistence in adoptive cell therapy Nat Rev Immunol 2021; 21: 769- 84.

[105] Saibil SD , St Paul M , Laister RC et al. Activation of peroxisome proliferator-activated receptors α and δ synergizes with inflammatory signals to enhance adoptive cell therapy Cancer Res 2019; 79: 445- 51.

[106] Kim D , Wu Y , Li Q et al. Nanoparticle-mediated lipid metabolic reprogramming of T cells in tumor microenvironments for immunometabolic therapy Nano-Micro Lett 2021; 13: 31.

[107] Conde E , Casares N , Mancheño U et al. FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma Mol Ther 2022; S1525-0016: 00505- 6.

[108] Lozano T , Conde E , Martín-Otal C et al. TCR-induced FOXP3 expression by CD8⁺ T cells impairs their anti-tumor activity Cancer Lett 2022; 528: 45- 58.

[109] Chang MR , Dharmarajan V , Doebelin C et al. Synthetic RORγt agonists enhance protective immunity ACS Chem Biol 2016; 11: 1012- 8.

[110] Hu X , Majchrzak K , Liu X et al. In vitro priming of adoptively transferred T cells with a RORγ agonist confers durable memory and stemness in vivo Cancer Res 2018; 78: 3888- 98.

[111] Zhao L , Liu Y , Zhao F et al. Inhibition of cholesterol esterification enzyme enhances the potency of human chimeric antigen receptor T cells against pancreatic carcinoma Mol Ther Oncolytics 2020; 16: 262- 71.

[112] Hao M , Hou S , Li W et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy Sci Transl Med 2020; 12: 571.

[113] Simoni Y , Becht E , Fehlings M et al. Bystander CD8⁺ T cells are abundant and phenotypically distinct in human tumour infiltrates Nature 2018; 557: 575- 9.

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2022 The Author(s) 2022. Published by Oxford University Press on behalf of Higher Education Press.