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Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
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Metabolic reprogramming of the tumor microenvironment to enhance immunotherapy

  • Seon Ah Lim (Department of Life Science, Ewha Womans University)
  • Received : 2024.02.05
  • Accepted : 2024.06.21
  • Published : 2024.09.30
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Abstract

Immunotherapy represents a promising treatment strategy for targeting various tumor types. However, the overall response rate is low due to the tumor microenvironment (TME). In the TME, numerous distinct factors actively induce immunosuppression, restricting the efficacy of anticancer immune reactions. Recently, metabolic reprogramming of tumors has been recognized for its role in modulating the tumor microenvironment to enhance immune cell responses in the TME. Furthermore, recent elucidations underscore the critical role of metabolic limitations imposed by the tumor microenvironment on the effectiveness of antitumor immune cells, guiding the development of novel immunotherapeutic approaches. Hence, achieving a comprehensive understanding of the metabolic requirements of both cancer and immune cells within the TME is pivotal. This insight not only aids in acknowledging the current limitations of clinical practices but also significantly shapes the trajectory of future research endeavors in the domain of cancer immunotherapy. In addition, therapeutic interventions targeting metabolic limitations have exhibited promising potential as combinatory treatments across diverse cancer types. In this review, we first discuss the metabolic barriers in the TME. Second, we explore how the immune response is regulated by metabolites. Finally, we will review the current strategy for targeting metabolism to not simply inhibit tumor growth but also enhance antitumor immune responses. Thus, we could suggest potent combination therapy for improving immunotherapy with metabolic inhibitors.

Keywords

Acknowledgement

This work was supported by the Ewha Womans University Research Grant of 2023 (1-2023-0406-001-1) and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2024-00336028).

References

  1. Pavlova NN and Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23, 27-47
  2. Hanahan D (2022) Hallmarks of cancer: new dimensions. Cancer Discov 12, 31-46
  3. Schiwitza A, Schildhaus HU, Zwerger B et al (2019) Monitoring efficacy of checkpoint inhibitor therapy in patients with non-small-cell lung cancer. Immunotherapy 11, 769-782
  4. Atkins MB and Tannir NM (2018) Current and emerging therapies for first-line treatment of metastatic clear cell renal cell carcinoma. Cancer Treat Rev 70, 127-137
  5. De Re V, Caggiari L, Repetto O, Mussolin L and Mascarin M (2019) Classical Hodgkin's lymphoma in the era of immune checkpoint inhibition. J Clin Med 8, 1596
  6. Han Y, Liu D and Li L (2020) PD-1/PD-L1 pathway: current researches in cancer. Am J Cancer Res 10, 727-742
  7. Morad G, Helmink BA, Sharma P and Wargo JA (2021) Hallmarks of response, resistance, and toxicity to immune checkpoint blockade. Cell 184, 5309-5337
  8. Conroy M and Naidoo J (2022) Immune-related adverse events and the balancing act of immunotherapy. Nat Commun 13, 392
  9. Xia L, Oyang L, Lin J et al (2021) The cancer metabolic reprogramming and immune response. Mol Cancer 20, 28
  10. Cong J, Wang X, Zheng X et al (2018) Dysfunction of natural killer cells by FBP1-induced inhibition of glycolysis during lung cancer progression. Cell Metab 28, 243-255 e245
  11. Ho PC, Bihuniak JD, Macintyre AN et al (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217-1228
  12. Spence AM, Muzi M, Graham MM et al (2002) 2-[(18)F] Fluoro-2-deoxyglucose and glucose uptake in malignant gliomas before and after radiotherapy: correlation with outcome. Clin Cancer Res 8, 971-979
  13. Guo H, Nan Y, Zhen Y et al (2016) miRNA-451 inhibits glioma cell proliferation and invasion by downregulating glucose transporter 1. Tumour Biol 37, 13751-13761
  14. Won WJ, Deshane JS, Leavenworth JW, Oliva CR and Griguer CE (2019) Metabolic and functional reprogramming of myeloid-derived suppressor cells and their therapeutic control in glioblastoma. Cell Stress 3, 47-65
  15. Raber P, Ochoa AC and Rodriguez PC (2012) Metabolism of L-arginine by myeloid-derived suppressor cells in cancer: mechanisms of T cell suppression and therapeutic perspectives. Immunol Invest 41, 614-634
  16. Brand A, Singer K, Koehl GE et al (2016) LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab 24, 657-671
  17. Watson MJ, Vignali PDA, Mullett SJ et al (2021) Metabolic support of tumour-infiltrating regulatory T cells by lactic acid. Nature 591, 645-651
  18. Feng Q, Liu Z, Yu X et al (2022) Lactate increases stem-ness of CD8 + T cells to augment anti-tumor immunity. Nat Commun 13, 4981
  19. Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E and Prendergast GC (2005) Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med 11, 312-319
  20. Opitz CA, Litzenburger UM, Sahm F et al (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478, 197-203
  21. Uyttenhove C, Pilotte L, Theate I et al (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 9, 1269-1274
  22. Pilotte L, Larrieu P, Stroobant V et al (2012) Reversal of tumoral immune resistance by inhibition of tryptophan 2,3- dioxygenase. Proc Natl Acad Sci U S A 109, 2497-2502
  23. Pallett LJ, Dimeloe S, Sinclair LV, Byrne AJ and Schurich A (2021) A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy. Immunother Adv 1, ltab010
  24. Altman BJ, Stine ZE and Dang CV (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16, 619-634
  25. Liu Y, Yang L, An H et al (2015) High expression of Solute Carrier Family 1, member 5 (SLC1A5) is associated with poor prognosis in clear-cell renal cell carcinoma. Sci Rep 5, 16954
  26. Lu J, Chen M, Tao Z et al (2017) Effects of targeting SLC1A5 on inhibiting gastric cancer growth and tumor development in vitro and in vivo. Oncotarget 8, 76458-76467
  27. Guerra L, Bonetti L and Brenner D (2020) Metabolic modulation of immunity: a new concept in cancer immunotherapy. Cell Rep 32, 107848
  28. Guo C, You Z, Shi H et al (2023) SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature 620, 200-208
  29. Chen CL, Hsu SC, Ann DK, Yen Y and Kung HJ (2021) Arginine signaling and cancer metabolism. Cancers (Basel) 13, 3541
  30. Rath M, Muller I, Kropf P, Closs EI and Munder M (2014) Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 5, 532
  31. Sun N and Zhao X (2022) Argininosuccinate synthase 1, arginine deprivation therapy and cancer management. Front Pharmacol 13, 935553
  32. Marti ILAA and Reith W (2021) Arginine-dependent immune responses. Cell Mol Life Sci 78, 5303-5324
  33. Geiger R, Rieckmann JC, Wolf T et al (2016) L-arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829-842 e813
  34. Lamas B, Vergnaud-Gauduchon J, Goncalves-Mendes N et al (2012) Altered functions of natural killer cells in response to L-arginine availability. Cell Immunol 280, 182-190
  35. Guerrero-Rodriguez SL, Mata-Cruz C, Perez-Tapia SM and Velasco-Velazquez MA (2022) Role of CD36 in cancer progression, stemness, and targeting. Front Cell Dev Biol 10, 1079076
  36. Feng WW, Wilkins O, Bang S et al (2019) CD36-mediated metabolic rewiring of breast cancer cells promotes resistance to HER2-targeted therapies. Cell Rep 29, 3405-3420 e3405
  37. Ladanyi A, Mukherjee A, Kenny HA et al (2018) Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene 37, 2285-2301
  38. Gharpure KM, Pradeep S, Sans M et al (2018) FABP4 as a key determinant of metastatic potential of ovarian cancer. Nat Commun 9, 2923
  39. Mukherjee A, Chiang CY, Daifotis HA et al (2020) Adipocyte-induced FABP4 expression in ovarian cancer cells promotes metastasis and mediates carboplatin resistance. Cancer Res 80, 1748-1761
  40. Nieman KM, Kenny HA, Penicka CV et al (2011) Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17, 1498-1503
  41. Zhu G, Guo N, Yong Y, Xiong Y and Tong Q (2019) Effect of 2-deoxy-D-glucose on gellan gum biosynthesis by Sphingomonas paucimobilis. Bioprocess Biosyst Eng 42, 897-900
  42. Dey S, Murmu N, Mondal T et al (2022) Multifaceted entrancing role of glucose and its analogue, 2-deoxy-Dglucose in cancer cell proliferation, inflammation, and virus infection. Biomed Pharmacother 156, 113801
  43. Sasawatari S, Okamoto Y, Kumanogoh A and Toyofuku T (2020) Blockade of N-glycosylation promotes antitumor immune response of T cells. J Immunol 204, 1373-1385
  44. Liu Y, Cao Y, Zhang W et al (2012) A small-molecule inhibitor of glucose transporter 1 downregulates glycolysis, induces cell-cycle arrest, and inhibits cancer cell growth in vitro and in vivo. Mol Cancer Ther 11, 1672-1682
  45. Siebeneicher H, Cleve A, Rehwinkel H et al (2016) Identification and optimization of the first highly selective GLUT1 inhibitor BAY-876. ChemMedChem 11, 2261-2271
  46. Oshima N, Ishida R, Kishimoto S et al (2020) Dynamic imaging of LDH inhibition in tumors reveals rapid in vivo metabolic rewiring and vulnerability to combination therapy. Cell Rep 30, 1798-1810 e1794
  47. Granchi C, Roy S, Giacomelli C et al (2011) Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells. J Med Chem 54, 1599-1612
  48. Maftouh M, Avan A, Sciarrillo R et al (2014) Synergistic interaction of novel lactate dehydrogenase inhibitors with gemcitabine against pancreatic cancer cells in hypoxia. Br J Cancer 110, 172-182
  49. Payen VL, Mina E, Van Hee VF, Porporato PE and Sonveaux P (2020) Monocarboxylate transporters in cancer. Mol Metab 33, 48-66
  50. Kober C, Roewe J, Schmees N et al (2023) Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy. J Immunother Cancer 11, e007495
  51. Reinfeld BI, Madden MZ, Wolf MM et al (2021) Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593, 282-288
  52. Schulte ML, Fu A, Zhao P et al (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24, 194-202
  53. Ma H, Wu Z, Peng J et al (2018) Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab. Int J Cancer 142, 2578-2588
  54. Nachef M, Ali AK, Almutairi SM and Lee SH (2021) Targeting SLC1A5 and SLC3A2/SLC7A5 as a potential strategy to strengthen anti-tumor immunity in the tumor microenvironment. Front Immunol 12, 624324
  55. Leone RD, Zhao L, Englert JM et al (2019) Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366, 1013-1021
  56. Oh MH, Sun IH, Zhao L et al (2020) Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J Clin Invest 130, 3865-3884
  57. Edwards DN, Ngwa VM, Raybuck AL et al (2021) Selective glutamine metabolism inhibition in tumor cells improves antitumor T lymphocyte activity in triple-negative breast cancer. J Clin Invest 131, e140100
  58. Kuzu OF, Noory MA and Robertson GP (2016) The role of cholesterol in cancer. Cancer Res 76, 2063-2070
  59. Nomura M, Liu J, Rovira II et al (2016) Fatty acid oxidation in macrophage polarization. Nat Immunol 17, 216-217
  60. Batista-Gonzalez A, Vidal R, Criollo A and Carreno LJ (2019) New insights on the role of lipid metabolism in the metabolic reprogramming of macrophages. Front Immunol 10, 2993
  61. Wang Z, Aguilar EG, Luna JI et al (2019) Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med 25, 141-151
  62. Qiu J, Villa M, Sanin DE et al (2019) Acetate promotes T cell effector function during glucose restriction. Cell Rep 27, 2063-2074.e5
  63. Wu J, Li G, Li L, Li D, Dong Z and Jiang P (2021) Asparagine enhances LCK signalling to potentiate CD8(+) T-cell activation and anti-tumour responses. Nat Cell Biol 23, 75-86
  64. Wang T, Gnanaprakasam JNR, Chen X et al (2020) Inosine is an alternative carbon source for CD8(+)-T-cell function under glucose restriction. Nat Metab 2, 635-647
  65. Amitrano AM and Kim M (2023) Metabolic challenges in anticancer CD8 T cell functions. Immune Netw 23, e9
  66. Triozzi PL, Stirling ER, Song Q et al (2022) Circulating immune bioenergetic, metabolic, and genetic signatures predict melanoma patients' response to anti-PD-1 immune checkpoint blockade. Clin Cancer Res 28, 1192-1202
  67. Varghese S, Pramanik S, Williams LJ et al (2021) The glutaminase inhibitor CB-839 (Telaglenastat) enhances the antimelanoma activity of T-cell-mediated immunotherapies. Mol Cancer Ther 20, 500-511
  68. Ma X, Xiao L, Liu L et al (2021) CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab 33, 1001-1012
  69. Lin R, Zhang H, Yuan Y et al (2020) Fatty acid oxidation controls CD8(+) tissue-resident memory T-cell survival in gastric adenocarcinoma. Cancer Immunol Res 8, 479-492
  70. Lim SA, Wei J, Nguyen TM et al (2021) Lipid signalling enforces functional specialization of T(reg) cells in tumours. Nature 591, 306-311
  71. Scharping NE, Menk AV, Whetstone RD, Zeng X and Delgoffe GM (2017) Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res 5, 9-16
  72. Afzal MZ, Mercado RR and Shirai K (2018) Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer 6, 64
  73. Afzal MZ, Dragnev K, Sarwar T and Shirai K (2019) Clinical outcomes in non-small-cell lung cancer patients receiving concurrent metformin and immune checkpoint inhibitors. Lung Cancer Manag 8, LMT11
  74. Kansal V, Burnham AJ, Kinney BLC et al (2023) Statin drugs enhance responses to immune checkpoint blockade in head and neck cancer models. J Immunother Cancer 11, e005940
  75. Zhang Y, Kurupati R, Liu L et al (2017) Enhancing CD8(+) T cell fatty acid catabolism within a metabolically challenging tumor microenvironment increases the efficacy of melanoma immunotherapy. Cancer Cell 32, 377-391.e9
  76. Chowdhury PS, Chamoto K, Kumar A and Honjo T (2018) 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 6, 1375-1387
  77. Schlaepfer IR and Joshi M (2020) CPT1A-mediated fat oxidation, mechanisms, and therapeutic potential. Endocrinology 161, bqz046
  78. Chamoto K, Chowdhury PS, Kumar A et al (2017) Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A 114, E761-E770
  79. Yang W, Bai Y, Xiong Y et al (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531, 651-655
  80. Sun X, Fan T, Sun G et al (2022) 2-Deoxy-D-glucose increases the sensitivity of glioblastoma cells to BCNU through the regulation of glycolysis, ROS and ERS pathways: in vitro and in vivo validation. Biochem Pharmacol 199, 115029
  81. Chan DA, Sutphin PD, Nguyen P et al (2011) Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3, 94ra70
  82. Guo L, Zhang W, Xie Y et al (2022) Diaminobutoxysubstituted isoflavonoid (DBI-1) enhances the therapeutic efficacy of GLUT1 inhibitor BAY-876 by modulating metabolic pathways in colon cancer cells. Mol Cancer Ther 21, 740-750
  83. Picard LK, Littwitz-Salomon E, Waldmann H and Watzl C (2022) Inhibition of glucose uptake blocks proliferation but not cytotoxic activity of NK cells. Cells 11, 3489
  84. Reckzeh ES, Karageorgis G, Schwalfenberg M et al (2019) Inhibition of glucose transporters and glutaminase synergistically impairs tumor cell growth. Cell Chem Biol 26, 1214-1228.e25
  85. Polanski R, Hodgkinson CL, Fusi A et al (2014) Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res 20, 926-937
  86. Panfili E, Mondanelli G, Orabona C et al (2023) The catalytic inhibitor epacadostat can affect the non-enzymatic function of IDO1. Front Immunol 14, 1134551
  87. Kuhajda FP, Pizer ES, Li JN, Mani NS, Frehywot GL and Townsend CA (2000) Synthesis and antitumor activity of an inhibitor of fatty acid synthase. Proc Natl Acad Sci U S A 97, 3450-3454
  88. Lemberg KM, Gori SS, Tsukamoto T, Rais R and Slusher BS (2022) Clinical development of metabolic inhibitors for oncology. J Clin Invest 132, e148550
  89. Ruiz-Perez MV, Sainero-Alcolado L, Oliynyk G et al (2021) Inhibition of fatty acid synthesis induces differentiation and reduces tumor burden in childhood neuroblastoma. iScience 24, 102128
  90. Feng J, Dai W, Mao Y et al (2020) Simvastatin re-sensitizes hepatocellular carcinoma cells to sorafenib by inhibiting HIF-1alpha/PPAR-gamma/PKM2-mediated glycolysis. J Exp Clin Cancer Res 39, 24