AI Chat Paper
Note: Please note that the following content is generated by AMiner AI. SciOpen does not take any responsibility related to this content.
{{lang === 'zh_CN' ? '文章概述' : 'Summary'}}
{{lang === 'en_US' ? '中' : 'Eng'}}
Chat more with AI
Powered by AMiner. Clicking this button will take you away from SciOpen.
Home Cancer Biology & Medicine Article
PDF (885.7 KB)
Cite
EndNote(RIS) BibTeX
Collect
Submit Manuscript AI Chat Paper
Show Outline
Outline
Show full outline
Hide outline
Outline
Show full outline
Hide outline
Review | Open Access

Metabolic regulation of immune responses to cancer

Jannis Wißfeld1,2,*, Anke Werner1,2,*, Xin Yan1,2,3,*, Nora ten Bosch1,2,*, Guoliang Cui1,2,3 ( )
Helmholtz Institute for Translational Oncology (HI-TRON), Mainz 55131, Germany
T Cell Metabolism Group (D192), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany

*These authors contributed equally to this work.

Show Author Information

Abstract

The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients—lipids and amino acids—in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of “editing” metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

Keywords

amino acidscancermetabolismLipidsanti-tumor immunityT cellsNK cellsimmunometabolism

References

1

Trauth BC, Klas C, Peters AMJ, Matzku S, Möller P, Falk W, et al. Monoclonal antibody-mediated tumor regression by induction of apoptosis. Science. 1989; 245: 301-5.
Crossref Google Scholar
2

Igney FH, Behrens CK, Krammer PH. CD95L mediates tumor counterattack in vitro but induces neutrophil-independent tumor rejection in vivo. Int J Cancer. 2005; 113: 78-87.
Crossref Google Scholar
3

Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. 2018; 359: 1350-5.
Crossref Google Scholar
4

Liu M, Sun Q, Wei F, Ren X. Comprehensive insights into the effects and regulatory mechanisms of immune cells expressing programmed death-1/programmed death ligand 1 in solid tumors. Cancer Biol Med. 2020; 17: 626-39.
Crossref Google Scholar
5

Baumann D, Hägele T, Mochayedi J, Drebant J, Vent C, Blobner S, et al. Proimmunogenic impact of MEK inhibition synergizes with agonist anti-CD40 immunostimulatory antibodies in tumor therapy. Nat Commun. 2020; 11: 2176.
Crossref Google Scholar
6

Suarez-Carmona M, Williams A, Schreiber J, Hohmann N, Pruefer U, Krauss J, et al. Combined inhibition of CXCL12 and PD-1 in MSS colorectal and pancreatic cancer: modulation of the microenvironment and clinical effects. J Immunother Cancer. 2021; 9.
Crossref Google Scholar
7

Hanna BS, Llaó-Cid L, Iskar M, Roessner PM, Klett LC, Wong JKL, et al. Interleukin-10 receptor signaling promotes the maintenance of a PD-1(int) TCF-1+ CD8+ T cell population that sustains anti-tumor immunity. Immunity. 2021; 54: 2825-41.e10.
Crossref Google Scholar
8

Weisshaar N, Wu J, Ming Y, Madi A, Hotz-Wagenblatt A, Ma S, et al. Rgs16 promotes antitumor CD8+ T cell exhaustion. Sci Immunol. 2022; 7: eabh1873.
Crossref Google Scholar
9

Pfister D, Núñez NG, Pinyol R, Govaere O, Pinter M, Szydlowska M, et al. NASH limits anti-tumour surveillance in immunotherapy-treated HCC. Nature. 2021; 592: 450-6.
Crossref Google Scholar
10

Dudek M, Pfister D, Donakonda S, Filpe P, Schneider A, Laschinger M, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature. 2021; 592: 444-9.
Crossref Google Scholar
11

Yuan D, Huang S, Berger E, Liu L, Gross N, Heinzmann F, et al. Kupffer cell-derived Tnf triggers cholangiocellular tumorigenesis through JNK due to chronic mitochondrial dysfunction and ROS. Cancer Cell. 2017; 31: 771-89.e6.
Crossref Google Scholar
12

Sektioglu IM, Carretero R, Bender N, Bogdan C, Garbi N, Umansky V, et al. Macrophage-derived nitric oxide initiates T-cell diapedesis and tumor rejection. Oncoimmunology. 2016; 5: e1204506.
Crossref Google Scholar
13

Madi A, Cui G. Regulation of immune cell metabolism by cancer cell oncogenic mutations. Int J Cancer. 2020; 147: 307-16.
Crossref Google Scholar
14

Xu S, Chaudhary O, Rodríguez-Morales P, Sun X, Chen D, Zappasodi R, 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.
Crossref Google Scholar
15

Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011; 478: 197-203.
Crossref Google Scholar
16

Sadik A, Somarribas Patterson LF, Öztürk S, Mohapatra SR, Panitz V, Secker PF, et al. IL4I1 is a metabolic immune checkpoint that activates the AHR and promotes tumor progression. Cell. 2020; 182: 1252-70.e34.
Crossref Google Scholar
17

Bunse L, Pusch S, Bunse T, Sahm F, Sanghvi K, Friedrich M, et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat Med. 2018; 24: 1192-203.
Crossref Google Scholar
18

Liu X, Zhao Y, Wu X, Liu Z, Liu X. A novel strategy to fuel cancer immunotherapy: targeting glucose metabolism to remodel the tumor microenvironment. Front Oncol. 2022; 12: 931104.
Crossref Google Scholar
19

Rangel Rivera GO, Knochelmann HM, Dwyer CJ, Smith AS, Wyatt MM, Rivera-Reyes AM, et al. Fundamentals of T cell metabolism and strategies to enhance cancer immunotherapy. Front Immunol. 2021; 12: 645242.
Crossref Google Scholar
20

Lim AR, Rathmell WK, Rathmell JC. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. Elife. 2020; 9: e55185.
Crossref Google Scholar
21

Terren I, Orrantia A, Vitalle J, Zenarruzabeitia O, Borrego F. NK cell metabolism and tumor microenvironment. Front Immunol. 2019; 10: 2278.
Crossref Google Scholar
22

Wu F, Cheng Y, Wu L, Zhang W, Zheng W, Wang Q, et al. Emerging landscapes of tumor immunity and metabolism. Front Oncol. 2020; 10: 575037.
Crossref Google Scholar
23

Butler LM, Perone Y, Dehairs J, Lupien LE, de Laat V, Talebi A, et al. Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev. 2020; 159: 245-93.
Crossref Google Scholar
24

Zhang Y, Kurupati R, Liu L, Zhou XY, Zhang G, Hudaihed A, 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.
Crossref Google Scholar
25

Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity. 2011; 35: 871-82.
Crossref Google Scholar
26

Chang C-H, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell. 2015; 162: 1229-41.
Crossref Google Scholar
27

Ho P-C, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell. 2015; 162: 1217-28.
Crossref Google Scholar
28

Chowdhury PS, Chamoto K, Kumar A, Honjo T. 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.
Crossref Google Scholar
29

Saibil SD, St Paul M, Laister RC, Garcia-Batres CR, Israni-Winger K, Elford AR, 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.
Crossref Google Scholar
30

Manzo T, Prentice BM, Anderson KG, Raman A, Schalck A, Codreanu GS, 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.
Crossref Google Scholar
31

Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun. 2015; 6: 6692.
Crossref Google Scholar
32

Zhang C, Yue C, Herrmann A, Song J, Egelston C, Wang T, 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.
Crossref Google Scholar
33

Blagih J, Coulombe F, Vincent Emma E, Dupuy F, Galicia-Vázquez G, Yurchenko E, et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 2015; 42: 41-54.
Crossref Google Scholar
34

Cham CM, Driessens G, O’Keefe JP, Gajewski TF. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8+ T cells. Eur J Immunol. 2008; 38: 2438-50.
Crossref Google Scholar
35

Cham CM, Gajewski TF. Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol. 2005; 174: 4670-7.
Crossref Google Scholar
36

Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, 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.
Crossref Google Scholar
37

Beier UH, Angelin A, Akimova T, Wang L, Liu Y, Xiao H, et al. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. FASEB J. 2015; 29: 2315-26.
Crossref Google Scholar
38

Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ, Nichols AG, et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol. 2016; 17: 1459-66.
Crossref Google Scholar
39

Angelin A, Gil-de-Gomez L, Dahiya S, Jiao J, Guo L, Levine MH, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017; 25: 1282-93 e7.
Crossref Google Scholar
40

Howie D, Cobbold SP, Adams E, Ten Bokum A, Necula AS, Zhang W, et al. Foxp3 drives oxidative phosphorylation and protection from lipotoxicity. JCI Insight. 2017; 2: e89160.
Crossref Google Scholar
41

Ma X, Bi E, Lu Y, Su P, Huang C, Liu L, et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 2019; 30: 143-56 e5.
Crossref Google Scholar
42

Wu J, Ma S, Sandhoff R, Ming Y, Hotz-Wagenblatt A, Timmerman V, et al. Loss of neurological disease HSAN-I-associated gene SPTLC2 impairs CD8+ T cell responses to infection by inhibiting T cell metabolic fitness. Immunity. 2019; 50: 1218-31.e5.
Crossref Google Scholar
43

Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature. 2016; 531: 651-5.
Crossref Google Scholar
44

Smyth MJ, Cretney E, Kelly JM, Westwood JA, Street SE, Yagita H, et al. Activation of NK cell cytotoxicity. Mol Immunol. 2005; 42: 501-10.
Crossref Google Scholar
45

Xue W, Zhang M. Updating targets for natural killer/T-cell lymphoma immunotherapy. Cancer Biol Med. 2021; 18: 52-62.
Crossref Google Scholar
46

Yaqoob P, Newsholme EA, Calder PC. Inhibition of natural killer cell activity by dietary lipids. Immunol Lett. 1994; 41: 241-7.
Crossref Google Scholar
47

Tobin LM, Mavinkurve M, Carolan E, Kinlen D, O’Brien EC, Little MA, et al. NK cells in childhood obesity are activated, metabolically stressed, and functionally deficient. JCI Insight. 2017; 2: e94939.
Crossref Google Scholar
48

Viel S, Besson L, Charrier E, Marcais A, Disse E, Bienvenu J, et al. Alteration of natural killer cell phenotype and function in obese individuals. Clin Immunol. 2017; 177: 12-7.
Crossref Google Scholar
49

Park A, Lee Y, Kim MS, Kang YJ, Park YJ, Jung H, et al. Prostaglandin E2 secreted by thyroid cancer cells contributes to immune escape through the suppression of natural killer (NK) cell cytotoxicity and NK cell differentiation. Front Immunol. 2018; 9: 1859.
Crossref Google Scholar
50

Ma X, Holt D, Kundu N, Reader J, Goloubeva O, Take Y, et al. A prostaglandin E (PGE) receptor EP4 antagonist protects natural killer cells from PGE 2-mediated immunosuppression and inhibits breast cancer metastasis. Oncoimmunology. 2013; 2: e22647.
Crossref Google Scholar
51

Kobayashi T, Lam PY, Jiang H, Bednarska K, Gloury R, Murigneux V, et al. Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment. Blood. 2020; 136: 3004-17.
Crossref Google Scholar
52

Michelet X, Dyck L, Hogan A, Loftus RM, Duquette D, Wei K, et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat Immunol. 2018; 19: 1330-40.
Crossref Google Scholar
53

Assmann N, O’Brien KL, Donnelly RP, Dyck L, Zaiatz-Bittencourt V, Loftus RM, et al. Srebp-controlled glucose metabolism is essential for nk cell functional responses. Nat Immunol. 2017; 18: 1197-206.
Crossref Google Scholar
54

Jensen TO, Schmidt H, Moller HJ, Hoyer M, Maniecki MB, Sjoegren P, et al. Macrophage markers in serum and tumor have prognostic impact in American Joint Committee on Cancer stage Ⅰ/Ⅱ melanoma. J Clin Oncol. 2009; 27: 3330-7.
Crossref Google Scholar
55

Kamper P, Bendix K, Hamilton-Dutoit S, Honore B, Nyengaard JR, d’Amore F. Tumor-infiltrating macrophages correlate with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma. Haematologica. 2011; 96: 269-76.
Crossref Google Scholar
56

Lee CH, Espinosa I, Vrijaldenhoven S, Subramanian S, Montgomery KD, Zhu S, et al. Prognostic significance of macrophage infiltration in leiomyosarcomas. Clin Cancer Res. 2008; 14: 1423-30.
Crossref Google Scholar
57

Medrek C, Ponten F, Jirstrom K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012; 12: 306.
Crossref Google Scholar
58

Zhang BC, Gao J, Wang J, Rao ZG, Wang BC, Gao JF. Tumor-associated macrophages infiltration is associated with peritumoral lymphangiogenesis and poor prognosis in lung adenocarcinoma. Med Oncol. 2011; 28: 1447-52.
Crossref Google Scholar
59

Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM. M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol. 2000; 164: 6166-73.
Crossref Google Scholar
60
Webpage biorad; macrophage polarization mini-review. 2020.
61

Stein M, Keshav S, Harris N, Gordon S. Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med. 1992; 176: 287-92.
Crossref Google Scholar
62

Martinez FO, Gordon S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 2014; 6: 13.
Crossref Google Scholar
63

Nathan CF, Murray HW, Wiebe ME, Rubin BY. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med. 1983; 158: 670-89.
Crossref Google Scholar
64

Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014; 513: 559-63.
Crossref Google Scholar
65

Su P, Wang Q, Bi E, Ma X, Liu L, Yang M, et al. Enhanced lipid accumulation and metabolism are required for the differentiation and activation of tumor-associated macrophages. Cancer Res. 2020; 80: 1438-50.
Crossref Google Scholar
66

Wang R, Lu M, Zhang J, Chen S, Luo X, Qin Y, et al. Increased IL-10 mRNA expression in tumor-associated macrophage correlated with late stage of lung cancer. J Exp Clin Cancer Res. 2011; 30: 62.
Crossref Google Scholar
67

Sica A, Saccani A, Bottazzi B, Polentarutti N, Vecchi A, van Damme J, et al. Autocrine production of IL-10 mediates defective IL-12 production and NF-kappa B activation in tumor-associated macrophages. J Immunol. 2000; 164: 762-7.
Crossref Google Scholar
68

Li L, Yang L, Wang L, Wang F, Zhang Z, Li J, et al. Impaired T cell function in malignant pleural effusion is caused by TGF-β derived predominantly from macrophages. Int J Cancer. 2016; 139: 2261-9.
Crossref Google Scholar
69

Peng J, Tsang JY, Li D, Niu N, Ho DH, Lau KF, et al. Inhibition of TGF-β signaling in combination with TLR7 ligation re-programs a tumoricidal phenotype in tumor-associated macrophages. Cancer Lett. 2013; 331: 239-49.
Crossref Google Scholar
70

Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; 10: 942-9.
Crossref Google Scholar
71

Lin EY, Li JF, Bricard G, Wang W, Deng Y, Sellers R, et al. Vascular endothelial growth factor restores delayed tumor progression in tumors depleted of macrophages. Mol Oncol. 2007; 1: 288-302.
Crossref Google Scholar
72

Lin EY, Li JF, Gnatovskiy L, Deng Y, Zhu L, Grzesik DA, et al. Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res. 2006; 66: 11238-46.
Crossref Google Scholar
73

Yeo EJ, Cassetta L, Qian BZ, Lewkowich I, Li JF, Stefater JA 3rd, et al. Myeloid WNT7b mediates the angiogenic switch and metastasis in breast cancer. Cancer Res. 2014; 74: 2962-73.
Crossref Google Scholar
74

Gocheva V, Wang HW, Gadea BB, Shree T, Hunter KE, Garfall AL, et al. IL-4 induces cathepsin protease activity in tumor-associated macrophages to promote cancer growth and invasion. Genes Dev. 2010; 24: 241-55.
Crossref Google Scholar
75

Vasiljeva O, Papazoglou A, Kruger A, Brodoefel H, Korovin M, Deussing J, et al. Tumor cell-derived and macrophage-derived cathepsin B promotes progression and lung metastasis of mammary cancer. Cancer Res. 2006; 66: 5242-50.
Crossref Google Scholar
76

Sabeh F, Ota I, Holmbeck K, Birkedal-Hansen H, Soloway P, Balbin M, et al. Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J Cell Biol. 2004; 167: 769-81.
Crossref Google Scholar
77

Wolf K, Wu YI, Liu Y, Geiger J, Tam E, Overall C, et al. Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion. Nat Cell Biol. 2007; 9: 893-904.
Crossref Google Scholar
78

Feng J, Han J, Pearce SF, Silverstein RL, Gotto AM Jr, Hajjar DP, et al. Induction of CD36 expression by oxidized LDL and IL-4 by a common signaling pathway dependent on protein kinase C and PPAR-gamma. J Lipid Res. 2000; 41: 688-96.
Crossref Google Scholar
79

Rios FJ, Koga MM, Pecenin M, Ferracini M, Gidlund M, Jancar S. Oxidized LDL induces alternative macrophage phenotype through activation of CD36 and PAFR. Mediators Inflamm. 2013; 2013: 198193.
Crossref Google Scholar
80

Nagy L, Tontonoz P, Alvarez JG, Chen H, Evans RM. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell. 1998; 93: 229-40.
Crossref Google Scholar
81

Masetti M, Carriero R, Portale F, Marelli G, Morina N, Pandini M, et al. Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer. J Exp Med. 2022; 219: e20210564.
Crossref Google Scholar
82

Divakaruni AS, Hsieh WY, Minarrieta L, Duong TN, Kim KKO, Desousa BR, et al. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metabolism. 2018; 28: 490-503.e7.
Crossref Google Scholar
83

Wu H, Han Y, Rodriguez Sillke Y, Deng H, Siddiqui S, Treese C, et al. Lipid droplet-dependent fatty acid metabolism controls the immune suppressive phenotype of tumor-associated macrophages. EMBO Mol Med. 2019; 11: e10698.
Crossref Google Scholar
84

Oishi Y, Spann NJ, Link VM, Muse ED, Strid T, Edillor C, et al. SREBP1 contributes to resolution of pro-inflammatory TLR4 signaling by reprogramming fatty acid metabolism. Cell Metab. 2017; 25: 412-27.
Crossref Google Scholar
85

Ramirez CM, Torrecilla-Parra M, Pardo-Marques V, de-Frutos MF, Perez-Garcia A, Tabraue C, et al. Crosstalk between LXR and caveolin-1 signaling supports cholesterol efflux and anti-inflammatory pathways in macrophages. Front Endocrinol (Lausanne) 2021; 12: 635923.
Crossref Google Scholar
86

Goossens P, Rodriguez-Vita J, Etzerodt A, Masse M, Rastoin O, Gouirand V, et al. Membrane cholesterol efflux drives tumor-associated macrophage reprogramming and tumor progression. Cell Metab. 2019; 29: 1376-89 e4.
Crossref Google Scholar
87

James BR, Tomanek-Chalkley A, Askeland EJ, Kucaba T, Griffith TS, Norian LA. Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth. J Immunol. 2012; 189: 1311-21.
Crossref Google Scholar
88

Weatherill AR, Lee JY, Zhao L, Lemay DG, Youn HS, Hwang DH. Saturated and polyunsaturated fatty acids reciprocally modulate dendritic cell functions mediated through TLR4. J Immunol 2005; 174: 5390-7.
Crossref Google Scholar
89

Zeyda M, Saemann MD, Stuhlmeier KM, Mascher DG, Nowotny PN, Zlabinger GJ, et al. Polyunsaturated fatty acids block dendritic cell activation and function independently of NF-kappaB activation. J Biol Chem. 2005; 280: 14293-301.
Crossref Google Scholar
90

Herber DL, Cao W, Nefedova Y, Novitskiy SV, Nagaraj S, Tyurin VA, et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010; 16: 880-6.
Crossref Google Scholar
91

Yi H, Yu X, Gao P, Wang Y, Baek SH, Chen X, et al. Pattern recognition scavenger receptor SRA/CD204 down-regulates toll-like receptor 4 signaling-dependent CD8 T-cell activation. Blood. 2009; 113: 5819-28.
Crossref Google Scholar
92

Ramakrishnan R, Tyurin VA, Veglia F, Condamine T, Amoscato A, Mohammadyani D, et al. Oxidized lipids block antigen cross-presentation by dendritic cells in cancer. J Immunol. 2014; 192: 2920-31.
Crossref Google Scholar
93

Cubillos-Ruiz JR, Silberman PC, Rutkowski MR, Chopra S, Perales-Puchalt A, Song M, et al. ER stress sensor XBP1 controls anti-tumor immunity by disrupting dendritic cell homeostasis. Cell. 2015; 161: 1527-38.
Crossref Google Scholar
94

Veglia F, Tyurin VA, Mohammadyani D, Blasi M, Duperret EK, Donthireddy L, et al. Lipid bodies containing oxidatively truncated lipids block antigen cross-presentation by dendritic cells in cancer. Nat Commun. 2017; 8: 2122.
Crossref Google Scholar
95

Wculek SK, Malanchi I. Neutrophils support lung colonization of metastasis-initiating breast cancer cells. Nature. 2015; 528: 413-7.
Crossref Google Scholar
96

Zhang Y, Guoqiang L, Sun M, Lu X. Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment. Cancer Biol Med. 2020; 17: 32-43.
Crossref Google Scholar
97

Li P, Lu M, Shi J, Gong Z, Hua L, Li Q, et al. Lung mesenchymal cells elicit lipid storage in neutrophils that fuel breast cancer lung metastasis. Nat Immunol. 2020; 21: 1444-55.
Crossref Google Scholar
98

Raccosta L, Fontana R, Maggioni D, Lanterna C, Villablanca EJ, Paniccia A, et al. The oxysterol-CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils. J Exp Med. 2013; 210: 1711-28.
Crossref Google Scholar
99

Chuang JC, Yu CL, Wang SR. Modulation of human lymphocyte proliferation by amino acids. Clin Exp Immunol. 1990; 81: 173-6.
Crossref Google Scholar
100

Hope HC, Salmond RJ. The role of non-essential amino acids in T cell function and anti-tumour immunity. Arch Immunol Ther Exp (Warsz). 2021; 69: 29.
Crossref Google Scholar
101

Han C, Ge M, Ho PC, Zhang L. Fueling T-cell antitumor immunity: amino acid metabolism revisited. Cancer Immunol Res. 2021; 9: 1373-82.
Crossref Google Scholar
102

Sullivan MR, Danai LV, Lewis CA, Chan SH, Gui DY, Kunchok T, et al. Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability. Elife. 2019; 8: e44235.
Crossref Google Scholar
103

Grzywa TM, Sosnowska A, Matryba P, Rydzynska Z, Jasinski M, Nowis D, et al. Myeloid cell-derived arginase in cancer immune response. Front Immunol. 2020; 11: 938.
Crossref Google Scholar
104

Morris SM, Jr. Arginine metabolism revisited. J Nutr. 2016; 146: 2579S-86S.
Crossref Google Scholar
105

Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell. 2016; 165: 153-64.
Crossref Google Scholar
106

Morris CR, Hamilton-Reeves J, Martindale RG, Sarav M, Ochoa Gautier JB. Acquired amino acid deficiencies: a focus on arginine and glutamine. Nutr Clin Pract. 2017; 32: 30s-47s.
Crossref Google Scholar
107

Husson A, Brasse-Lagnel C, Fairand A, Renouf S, Lavoinne A. Argininosuccinate synthetase from the urea cycle to the citrulline-NO cycle. Eur J Biochem. 2003; 270: 1887-99.
Crossref Google Scholar
108

Böger RH. The pharmacodynamics of L-arginine. J Nutr. 2007; 137: 1650S-5S.
Crossref Google Scholar
109

Lüneburg N, Xanthakis V, Schwedhelm E, Sullivan LM, Maas R, Anderssohn M, et al. Reference intervals for plasma L-arginine and the L-arginine: asymmetric dimethylarginine ratio in the framingham offspring cohort. J Nutr. 2011; 141: 2186-90.
Crossref Google Scholar
110

Steggerda SM, Bennett MK, Chen J, Emberley E, Huang T, Janes JR, et al. Inhibition of arginase by CB-1158 blocks myeloid cell-mediated immune suppression in the tumor microenvironment. J Immunother Cancer. 2017; 5: 101.
Crossref Google Scholar
111

Mussai F, Wheat R, Sarrou E, Booth S, Stavrou V, Fultang L, et al. Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. Int J Cancer. 2019; 145: 2201-8.
Crossref Google Scholar
112

Mussai F, Egan S, Higginbotham-Jones J, Perry T, Beggs A, Odintsova E, et al. Arginine dependence of acute myeloid leukemia blast proliferation: a novel therapeutic target. Blood. 2015; 125: 2386-96.
Crossref Google Scholar
113

Pan M, Reid MA, Lowman XH, Kulkarni RP, Tran TQ, Liu X, et al. Regional glutamine deficiency in tumours promotes dedifferentiation through inhibition of histone demethylation. Nat Cell Biol. 2016; 18: 1090-101.
Crossref Google Scholar
114

Mussai F, De Santo C, Abu-Dayyeh I, Booth S, Quek L, McEwen-Smith RM, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment. Blood. 2013; 122: 749-58.
Crossref Google Scholar
115

Liu Y, Van Ginderachter JA, Brys L, De Baetselier P, Raes G, Geldhof AB. Nitric oxide-independent CTL suppression during tumor progression: association with arginase-producing (M2) myeloid cells. J Immunol. 2003; 170: 5064-74.
Crossref Google Scholar
116

Gray MJ, Poljakovic M, Kepka-Lenhart D, Morris SM. Induction of arginase I transcription by IL-4 requires a composite DNA response element for STAT6 and C/EBPβ. Gene. 2005; 353: 98-106.
Crossref Google Scholar
117

Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, et al. Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U S A. 2009; 106: 12055-60.
Crossref Google Scholar
118

Doedens AL, Stockmann C, Rubinstein MP, Liao D, Zhang N, DeNardo DG, et al. Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression. Cancer Res. 2010; 70: 7465-75.
Crossref Google Scholar
119

Rodriguez PC, Zea AH, DeSalvo J, Culotta KS, Zabaleta J, Quiceno DG, et al. L-arginine consumption by macrophages modulates the expression of CD3 zeta chain in T lymphocytes. J Immunol. 2003; 171: 1232-9.
Crossref Google Scholar
120

Rodriguez PC, Quiceno DG, Zabaleta J, Ortiz B, Zea AH, Piazuelo MB, et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T-cell receptor expression and antigen-specific T-cell responses. Cancer Res. 2004; 64: 5839-49.
Crossref Google Scholar
121

Rodriguez PC, Ernstoff MS, Hernandez C, Atkins M, Zabaleta J, Sierra R, et al. Arginase I–producing myeloid-derived suppressor cells in renal cell carcinoma are a subpopulation of activated granulocytes. Cancer Res. 2009; 69: 1553-60.
Crossref Google Scholar
122

Crump NT, Hadjinicolaou AV, Xia M, Walsby-Tickle J, Gileadi U, Chen J-L, et al. Chromatin accessibility governs the differential response of cancer and T cells to arginine starvation. Cell Rep. 2021; 35: 109101.
Crossref Google Scholar
123

Zea AH, Rodriguez PC, Culotta KS, Hernandez CP, DeSalvo J, Ochoa JB, et al. L-arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes. Cell Immunol. 2004; 232: 21-31.
Crossref Google Scholar
124

Munder M. Suppression of T-cell functions by human granulocyte arginase. Blood. 2006; 108: 1627-34.
Crossref Google Scholar
125

Fletcher M, Ramirez ME, Sierra RA, Raber P, Thevenot P, Al-Khami AA, et al. L-arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 2015; 75: 275-83.
Crossref Google Scholar
126

Werner A, Koschke M, Leuchtner N, Luckner-Minden C, Habermeier A, Rupp J, et al. Reconstitution of T cell proliferation under arginine limitation: activated human T cells take up citrulline via l-type amino acid transporter 1 and use it to regenerate arginine after induction of argininosuccinate synthase expression. Front Immunol. 2017; 8: 864.
Crossref Google Scholar
127

Werner A, Amann E, Schnitzius V, Habermeier A, Luckner-Minden C, Leuchtner N, et al. Induced arginine transport via cationic amino acid transporter-1 is necessary for human T-cell proliferation. Eur J Immunol. 2016; 46: 92-103.
Crossref Google Scholar
128

Geiger R, Rieckmann JC, Wolf T, Basso C, Feng Y, Fuhrer T, et al. L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell. 2016; 167: 829-42.e13.
Crossref Google Scholar
129

Rodriguez PC, Quiceno DG, Ochoa AC. L-arginine availability regulates T-lymphocyte cell-cycle progression. Blood. 2007; 109: 1568-73.
Crossref Google Scholar
130

Baniyash M. TCR ζ-chain downregulation: curtailing an excessive inflammatory immune response. Nat Rev Immunol. 2004; 4: 675-87.
Crossref Google Scholar
131

Huppa JB, Davis MM. T-cell-antigen recognition and the immunological synapse. Nat Rev Immunol. 2003; 3: 973-83.
Crossref Google Scholar
132

Eibert SM, Lee K-H, Pipkorn R, Sester U, Wabnitz GH, Giese T, et al. Cofilin peptide homologs interfere with immunological synapse formation and T cell activation. Proc Natl Acad Sci. 2004; 101: 1957-62.
Crossref Google Scholar
133

Feldmeyer N, Wabnitz G, Leicht S, Luckner-Minden C, Schiller M, Franz T, et al. Arginine deficiency leads to impaired cofilin dephosphorylation in activated human T lymphocytes. Int Immunol. 2012; 24: 303-13.
Crossref Google Scholar
134

Zhang J, Xu X, Shi M, Chen Y, Yu D, Zhao C, et al. CD13(hi) neutrophil-like myeloid-derived suppressor cells exert immune suppression through arginase 1 expression in pancreatic ductal adenocarcinoma. Oncoimmunology. 2017; 6: e1258504.
Crossref Google Scholar
135

Mao F-Y, Zhao Y-l, Lv Y-P, Teng Y-S, Kong H, Liu Y-G, et al. CD45+CD33lowCD11bdim myeloid-derived suppressor cells suppress CD8+ T cell activity via the IL-6/IL-8-arginase I axis in human gastric cancer. Cell Death Dis. 2018; 9: 763.
Crossref Google Scholar
136

Vonwirth V, Bulbul Y, Werner A, Echchannaoui H, Windschmitt J, Habermeier A, et al. Inhibition of arginase 1 liberates potent T cell immunostimulatory activity of human neutrophil granulocytes. Front Immunol. 2020; 11: 617699.
Crossref Google Scholar
137

Lamas B, Vergnaud-Gauduchon J, Goncalves-Mendes N, Perche O, Rossary A, Vasson MP, et al. Altered functions of natural killer cells in response to L-arginine availability. Cell Immunol. 2012; 280: 182-90.
Crossref Google Scholar
138

Oberlies J, Watzl C, Giese T, Luckner C, Kropf P, Muller I, et al. Regulation of NK cell function by human granulocyte arginase. J Immunol. 2009; 182: 5259-67.
Crossref Google Scholar
139

Westhaver LP, Nersesian S, Nelson A, MacLean LK, Carter EB, Rowter D, et al. Mitochondrial damage-associated molecular patterns trigger arginase-dependent lymphocyte immunoregulation. Cell Rep. 2022; 39: 110847.
Crossref Google Scholar
140

Jain A, Bakhshi S, Thakkar H, Gerards M, Singh A. Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: a potential biomarker for predicting inferior survival. Pediatr Blood Cancer. 2018; 65: e26874.
Crossref Google Scholar
141

Meng X, Schwarzenbach H, Yang Y, Müller V, Li N, Tian D, et al. Circulating mitochondrial DNA is linked to progression and prognosis of epithelial ovarian cancer. Transl Oncol. 2019; 12: 1213-20.
Crossref Google Scholar
142

Comai S, Bertazzo A, Brughera M, Crotti S. Tryptophan in health and disease. Adv Clin Chem. 2020; 95: 165-218.
Crossref Google Scholar
143

Liu X, Shin N, Koblish HK, Yang G, Wang Q, Wang K, et al. Selective inhibition of IDO1 effectively regulates mediators of antitumor immunity. Blood. 2010; 115: 3520-30.
Crossref Google Scholar
144

Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, Mellor AL. Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med. 1999; 189: 1363-72.
Crossref Google Scholar
145

Platten M, Nollen EAA, Rohrig UF, Fallarino F, Opitz CA. Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond. Nat Rev Drug Discov. 2019; 18: 379-401.
Crossref Google Scholar
146

Theate I, van Baren N, Pilotte L, Moulin P, Larrieu P, Renauld JC, et al. Extensive profiling of the expression of the indoleamine 2,3-dioxygenase 1 protein in normal and tumoral human tissues. Cancer Immunol Res. 2015; 3: 161-72.
Crossref Google Scholar
147

Frumento G, Rotondo R, Tonetti M, Damonte G, Benatti U, Ferrara GB. Tryptophan-derived catabolites are responsible for inhibition of T and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med. 2002; 196: 459-68.
Crossref Google Scholar
148

Peyraud F, Guegan J-P, Bodet D, Cousin S, Bessede A, Italiano A. Targeting tryptophan catabolism in cancer immunotherapy era: challenges and perspectives. Front Immunol. 2022; 13: 807271.
Crossref Google Scholar
149

Puccetti P, Fallarino F, Italiano A, Soubeyran I, MacGrogan G, Debled M, et al. Accumulation of an endogenous tryptophan-derived metabolite in colorectal and breast cancers. PLoS One. 2015; 10: e0122046.
Crossref Google Scholar
150

Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, Vacca C, et al. The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol. 2006; 176: 6752-61.
Crossref Google Scholar
151

Fallarino F, Grohmann U, Hwang KW, Orabona C, Vacca C, Bianchi R, et al. Modulation of tryptophan catabolism by regulatory T cells. Nat Immunol. 2003; 4: 1206-12.
Crossref Google Scholar
152

Costa-Mattioli M, Walter P. The integrated stress response: from mechanism to disease. Science. 2020; 368: eaat5314.
Crossref Google Scholar
153

Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. Gcn2 kinase in t cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005; 22: 633-42.
Crossref Google Scholar
154

Sonner JK, Deumelandt K, Ott M, Thome CM, Rauschenbach KJ, Schulz S, et al. The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas. Oncoimmunology. 2016; 5: e1240858.
Crossref Google Scholar
155

Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008; 181: 5396-404.
Crossref Google Scholar
156

Curti A, Pandolfi S, Valzasina B, Aluigi M, Isidori A, Ferri E, et al. Modulation of tryptophan catabolism by human leukemic cells results in the conversion of CD25- into CD25+ T regulatory cells. Blood. 2007; 109: 2871-7.
Crossref Google Scholar
157

Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010; 185: 3190-8.
Crossref Google Scholar
158

Stockinger B, Di Meglio P, Gialitakis M, Duarte JH. The aryl hydrocarbon receptor: multitasking in the immune system. Annu Rev Immunol. 2014; 32: 403-32.
Crossref Google Scholar
159

Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, et al. Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation. Cancer Cell. 2018; 33: 480-94.e7.
Crossref Google Scholar
160

Amobi-McCloud A, Muthuswamy R, Battaglia S, Yu H, Liu T, Wang J, et al. IDO1 expression in ovarian cancer induces PD-1 in T cells via aryl hydrocarbon receptor activation. Front Immunol. 2021; 12: 678999.
Crossref Google Scholar
161

Novikov O, Wang Z, Stanford EA, Parks AJ, Ramirez-Cardenas A, Landesman E, et al. An aryl hydrocarbon receptor-mediated amplification loop that enforces cell migration in ER-/PR-/Her2- human breast cancer cells. Mol Pharmacol. 2016; 90: 674-88.
Crossref Google Scholar
162

DiNatale BC, Murray IA, Schroeder JC, Flaveny CA, Lahoti TS, Laurenzana EM, et al. Kynurenic acid is a potent endogenous aryl hydrocarbon receptor ligand that synergistically induces interleukin-6 in the presence of inflammatory signaling. Toxicol Sci. 2010; 115: 89-97.
Crossref Google Scholar
163

Caforio M, Sorino C, Caruana I, Weber G, Camera A, Cifaldi L, et al. GD2 redirected CAR T and activated NK-cell-mediated secretion of ifngamma overcomes MYCN-dependent IDO1 inhibition, contributing to neuroblastoma cell immune escape. J Immunother Cancer. 2021; 9: e001502.
Crossref Google Scholar
164

Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKP46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006; 108: 4118-25.
Crossref Google Scholar
165

Wang D, Saga Y, Mizukami H, Sato N, Nonaka H, Fujiwara H, et al. Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy. Int J Oncol. 2012; 40: 929-34.
Crossref Google Scholar
Cancer Biology & Medicine
Volume 19 Issue 11,
November 2022
Pages 1528-1542
DOI: 10.20892/j.issn.2095-3941.2022.0381
Cite this article:
Wißfeld J, Werner A, Yan X, et al. Metabolic regulation of immune responses to cancer. Cancer Biology & Medicine, 2022, 19(11): 1528-1542. https://doi.org/10.20892/j.issn.2095-3941.2022.0381

158

Views

1

Downloads

1

Crossref

11

Web of Science

11

Scopus

Altmetrics
Received: 05 July 2022
Accepted: 15 September 2022
Published: 05 December 2022
©2022 Cancer Biology & Medicine.

Creative Commons Attribution-NonCommercial 4.0 International License
Return