BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

A new aspect of an old friend: the beneficial effect of metformin on anti-tumor immunity

  • Kim, KyeongJin (Department of Biomedical Sciences, College of Medicine, Inha University) ;
  • Yang, Wen-Hao (Graduate Institute of Biomedical Sciences, China Medical University) ;
  • Jung, Youn-Sang (Department of Life Science, Chung-Ang University) ;
  • Cha, Jong-ho (Department of Biomedical Sciences, College of Medicine, Inha University)
  • Received : 2020.07.10
  • Published : 2020.10.31
Download PDF
⟨ Previous Next ⟩

Abstract

T-cell-based cancer immunotherapies, such as immune checkpoint blockers (ICBs) and chimeric antigen receptor (CAR)-T-cells, have significant anti-tumor effects against certain types of cancer, providing a new paradigm for cancer treatment. However, the activity of tumor infiltrating T-cells (TILs) can be effectively neutralized in the tumor microenvironment (TME) of most solid tumors, rich in various immunosuppressive factors and cells. Therefore, to improve the clinical outcomes of established T-cell-based immunotherapy, adjuvants that can comprehensively relieve multiple immunosuppressive mechanisms of TME are needed. In this regard, recent studies have revealed that metformin has several beneficial effects on anti-tumor immunity. In this mini-review, we understand the immunosuppressive properties of TME and how metformin comprehensively enhances anti-tumor immunity. Finally, we will discuss this old friend's potential as an adjuvant for cancer immunotherapy.

Keywords

References

  1. Irons BK and Minze MG (2014) Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes Metab Syndr Obes 7, 15-24 https://doi.org/10.2147/DMSO.S38753
  2. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR and Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330, 1304-1305 https://doi.org/10.1136/bmj.38415.708634.F7
  3. Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M and Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 122, 253-270 https://doi.org/10.1042/CS20110386
  4. Aljofan M and Riethmacher D (2019) Anticancer activity of metformin: a systematic review of the literature. Future Sci OA 5, FSO410
  5. Dowling RJ, Zakikhani M, Fantus IG, Pollak M and Sonenberg N (2007) Metformin inhibits mammalian target of rapamycin-dependent translation initiation in breast cancer cells. Cancer Res 67, 10804-10812 https://doi.org/10.1158/0008-5472.CAN-07-2310
  6. Andrzejewski S, Siegel PM and St-Pierre J (2018) Metabolic Profiles Associated With Metformin Efficacy in Cancer. Front Endocrinol (Lausanne) 9, 372 https://doi.org/10.3389/fendo.2018.00372
  7. Tseng HW, Li SC and Tsai KW (2019) Metformin Treatment Suppresses Melanoma Cell Growth and Motility Through Modulation of microRNA Expression. Cancers (Basel) 11, 209 https://doi.org/10.3390/cancers11020209
  8. Deng XS, Wang S, Deng A et al (2012) Metformin targets Stat3 to inhibit cell growth and induce apoptosis in triple-negative breast cancers. Cell Cycle 11, 367-376 https://doi.org/10.4161/cc.11.2.18813
  9. Feng Y, Ke C, Tang Q et al (2014) Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis 5, e1088 https://doi.org/10.1038/cddis.2014.59
  10. Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E and Udono H (2015) Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A 112, 1809-1814 https://doi.org/10.1073/pnas.1417636112
  11. Cha JH, Yang WH, Xia W et al (2018) Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Mol Cell 71, 606-620 e607 https://doi.org/10.1016/j.molcel.2018.07.030
  12. Garcia EY (1950) Flumamine, a new synthetic analgesic and anti-flu drug. J Philipp Med Assoc 26, 287-293
  13. Zhang Z, Li F, Tian Y et al (2020) Metformin Enhances the Antitumor Activity of CD8(+) T Lymphocytes via the AMPKmiR-107-Eomes-PD-1 Pathway. J Immunol 204, 2575-2588 https://doi.org/10.4049/jimmunol.1901213
  14. Cha JH, Chan LC, Song MS and Hung MC (2019) New Approaches on Cancer Immunotherapy. Cold Spring Harb Perspect Med 10, a036863
  15. Del Barco S, Vazquez-Martin A, Cufi S et al (2011) Metformin: multi-faceted protection against cancer. Oncotarget 2, 896-917 https://doi.org/10.18632/oncotarget.387
  16. Basu AK (2018) DNA Damage, Mutagenesis and Cancer. Int J Mol Sci 19, 970 https://doi.org/10.3390/ijms19040970
  17. Hyndman IJ (2016) Review: the Contribution of both Nature and Nurture to Carcinogenesis and Progression in Solid Tumours. Cancer Microenviron 9, 63-69 https://doi.org/10.1007/s12307-016-0183-4
  18. Mittal D, Gubin MM, Schreiber RD and Smyth MJ (2014) New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol 27, 16-25 https://doi.org/10.1016/j.coi.2014.01.004
  19. Paul S and Lal G (2017) The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Front Immunol 8, 1124 https://doi.org/10.3389/fimmu.2017.01124
  20. Reeves E and James E (2017) Antigen processing and immune regulation in the response to tumours. Immunology 150, 16-24 https://doi.org/10.1111/imm.12675
  21. Kim R, Emi M and Tanabe K (2007) Cancer immunoediting from immune surveillance to immune escape. Immunology 121, 1-14 https://doi.org/10.1111/j.1365-2567.2007.02587.x
  22. de Charette M, Marabelle A and Houot R (2016) Turning tumour cells into antigen presenting cells: The next step to improve cancer immunotherapy? Eur J Cancer 68, 134-147 https://doi.org/10.1016/j.ejca.2016.09.010
  23. Halenius A, Gerke C and Hengel H (2015) Classical and non-classical MHC I molecule manipulation by human cytomegalovirus: so many targets-but how many arrows in the quiver? Cell Mol Immunol 12, 139-153 https://doi.org/10.1038/cmi.2014.105
  24. Kochan G, Escors D, Breckpot K and Guerrero-Setas D (2013) Role of non-classical MHC class I molecules in cancer immunosuppression. Oncoimmunology 2, e26491 https://doi.org/10.4161/onci.26491
  25. Balkwill FR, Capasso M and Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125, 5591-5596 https://doi.org/10.1242/jcs.116392
  26. Gajewski TF, Schreiber H and Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14, 1014-1022 https://doi.org/10.1038/ni.2703
  27. Wang M, Zhao J, Zhang L et al (2017) Role of tumor microenvironment in tumorigenesis. J Cancer 8, 761-773 https://doi.org/10.7150/jca.17648
  28. Quail DF and Joyce JA (2013) Microenvironmental regulation of tumor progression and metastasis. Nat Med 19, 1423-1437 https://doi.org/10.1038/nm.3394
  29. Kambayashi T and Laufer TM (2014) Atypical MHC class II-expressing antigen-presenting cells: can anything replace a dendritic cell? Nat Rev Immunol 14, 719-730 https://doi.org/10.1038/nri3754
  30. Hagemann T, Balkwill F and Lawrence T (2007) Inflammation and cancer: a double-edged sword. Cancer Cell 12, 300-301 https://doi.org/10.1016/j.ccr.2007.10.005
  31. Zitvogel L, Pietrocola F and Kroemer G (2017) Nutrition, inflammation and cancer. Nat Immunol 18, 843-850 https://doi.org/10.1038/ni.3754
  32. Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4, 11-22 https://doi.org/10.1038/nrc1252
  33. Poh AR and Ernst M (2018) Targeting Macrophages in Cancer: From Bench to Bedside. Front Oncol 8, 49 https://doi.org/10.3389/fonc.2018.00049
  34. Landskron G, De la Fuente M, Thuwajit P, Thuwajit C and Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014, 149185 https://doi.org/10.1155/2014/149185
  35. D'Elia RV, Harrison K, Oyston PC, Lukaszewski RA and Clark GC (2013) Targeting the "cytokine storm" for therapeutic benefit. Clin Vaccine Immunol 20, 319-327 https://doi.org/10.1128/CVI.00636-12
  36. Kumar V, Patel S, Tcyganov E and Gabrilovich DI (2016) The Nature of Myeloid-Derived Suppressor Cells in the Tumor Microenvironment. Trends Immunol 37, 208-220 https://doi.org/10.1016/j.it.2016.01.004
  37. Hanson EM, Clements VK, Sinha P, Ilkovitch D and Ostrand-Rosenberg S (2009) Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol 183, 937-944 https://doi.org/10.4049/jimmunol.0804253
  38. Crusz SM and Balkwill FR (2015) Inflammation and cancer: advances and new agents. Nat Rev Clin Oncol 12, 584-596 https://doi.org/10.1038/nrclinonc.2015.105
  39. Brasky TM, Potter JD, Kristal AR et al (2012) Non-steroidal anti-inflammatory drugs and cancer incidence by sex in the VITamins And Lifestyle (VITAL) cohort. Cancer Causes Control 23, 431-444 https://doi.org/10.1007/s10552-011-9891-8
  40. Liu Y, Chen JQ, Xie L et al (2014) Effect of aspirin and other non-steroidal anti-inflammatory drugs on prostate cancer incidence and mortality: a systematic review and meta-analysis. BMC Med 12, 55 https://doi.org/10.1186/1741-7015-12-55
  41. Nath N, Khan M, Paintlia MK, Singh I, Hoda MN and Giri S (2009) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182, 8005-8014 https://doi.org/10.4049/jimmunol.0803563
  42. Triggle CR and Ding H (2014) Cardiovascular impact of drugs used in the treatment of diabetes. Ther Adv Chronic Dis 5, 245-268 https://doi.org/10.1177/2040622314546125
  43. Lund SS, Tarnow L, Stehouwer CD et al (2008) Impact of metformin versus repaglinide on non-glycaemic cardiovascular risk markers related to inflammation and endothelial dysfunction in non-obese patients with type 2 diabetes. Eur J Endocrinol 158, 631-641 https://doi.org/10.1530/EJE-07-0815
  44. Huang NL, Chiang SH, Hsueh CH, Liang YJ, Chen YJ and Lai LP (2009) Metformin inhibits TNF-alpha-induced IkappaB kinase phosphorylation, IkappaB-alpha degradation and IL-6 production in endothelial cells through PI3K-dependent AMPK phosphorylation. Int J Cardiol 134, 169-175 https://doi.org/10.1016/j.ijcard.2008.04.010
  45. Ersoy C, Kiyici S, Budak F et al (2008) The effect of metformin treatment on VEGF and PAI-1 levels in obese type 2 diabetic patients. Diabetes Res Clin Pract 81, 56-60 https://doi.org/10.1016/j.diabres.2008.02.006
  46. Kelly B, Tannahill GM, Murphy MP and O'Neill LA (2015) Metformin Inhibits the Production of Reactive Oxygen Species from NADH:Ubiquinone Oxidoreductase to Limit Induction of Interleukin-1beta (IL-1beta) and Boosts Interleukin- 10 (IL-10) in Lipopolysaccharide (LPS)-activated Macrophages. J Biol Chem 290, 20348-20359 https://doi.org/10.1074/jbc.M115.662114
  47. Wang JC, Sun X, Ma Q et al (2018) Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization. J Cell Mol Med 22, 3825-3836 https://doi.org/10.1111/jcmm.13655
  48. Qin G, Lian J, Huang L et al (2018) Metformin blocks myeloid-derived suppressor cell accumulation through AMPK-DACH1-CXCL1 axis. Oncoimmunology 7, e1442167 https://doi.org/10.1080/2162402X.2018.1442167
  49. Semenza GL (2016) The hypoxic tumor microenvironment: A driving force for breast cancer progression. Biochim Biophys Acta 1863, 382-391 https://doi.org/10.1016/j.bbamcr.2015.05.036
  50. Brown JM (1999) The hypoxic cell: a target for selective cancer therapy--eighteenth Bruce F. Cain Memorial Award lecture. Cancer Res 59, 5863-5870
  51. Eales KL, Hollinshead KE and Tennant DA (2016) Hypoxia and metabolic adaptation of cancer cells. Oncogenesis 5, e190 https://doi.org/10.1038/oncsis.2015.50
  52. Weidemann A and Johnson RS (2008) Biology of HIF-1alpha. Cell Death Differ 15, 621-627 https://doi.org/10.1038/cdd.2008.12
  53. Subarsky P and Hill RP (2003) The hypoxic tumour microenvironment and metastatic progression. Clin Exp Metastasis 20, 237-250 https://doi.org/10.1023/A:1022939318102
  54. Noman MZ, Messai Y, Carre T et al (2011) Microenvironmental hypoxia orchestrating the cell stroma cross talk, tumor progression and antitumor response. Crit Rev Immunol 31, 357-377 https://doi.org/10.1615/CritRevImmunol.v31.i5.10
  55. Clambey ET, McNamee EN, Westrich JA et al (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 109, E2784-2793 https://doi.org/10.1073/pnas.1202366109
  56. Mancino A, Schioppa T, Larghi P et al (2008) Divergent effects of hypoxia on dendritic cell functions. Blood 112, 3723-3734 https://doi.org/10.1182/blood.v112.11.3723.3723
  57. Vuillefroy de Silly R, Dietrich PY and Walker PR (2016) Hypoxia and antitumor CD8+ T cells: An incompatible alliance? Oncoimmunology 5, e1232236 https://doi.org/10.1080/2162402X.2016.1232236
  58. Wang JC, Li GY, Li PP et al (2017) Suppression of hypoxia-induced excessive angiogenesis by metformin via elevating tumor blood perfusion. Oncotarget 8, 73892-73904 https://doi.org/10.18632/oncotarget.18029
  59. Zhou X, Chen J, Yi G et al (2016) Metformin suppresses hypoxia-induced stabilization of HIF-1alpha through reprogramming of oxygen metabolism in hepatocellular carcinoma. Oncotarget 7, 873-884 https://doi.org/10.18632/oncotarget.6418
  60. Guimaraes TA, Farias LC, Santos ES et al (2016) Metformin increases PDH and suppresses HIF-1alpha under hypoxic conditions and induces cell death in oral squamous cell carcinoma. Oncotarget 7, 55057-55068 https://doi.org/10.18632/oncotarget.10842
  61. 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 https://doi.org/10.1158/2326-6066.CIR-16-0103
  62. Thompson RH, Gillett MD, Cheville JC et al (2004) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci U S A 101, 17174-17179 https://doi.org/10.1073/pnas.0406351101
  63. Zhang M, Li G, Wang Y et al (2017) PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis. Sci Rep 7, 10255 https://doi.org/10.1038/s41598-017-10925-7
  64. Brody R, Zhang Y, Ballas M et al (2017) PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review. Lung Cancer 112, 200-215 https://doi.org/10.1016/j.lungcan.2017.08.005
  65. Li J, Wang P and Xu Y (2017) Prognostic value of programmed cell death ligand 1 expression in patients with head and neck cancer: A systematic review and metaanalysis. PLoS One 12, e0179536 https://doi.org/10.1371/journal.pone.0179536
  66. Schildberg FA, Klein SR, Freeman GJ and Sharpe AH (2016) Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family. Immunity 44, 955-972 https://doi.org/10.1016/j.immuni.2016.05.002
  67. Pardoll DM (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 12, 252-264 https://doi.org/10.1038/nrc3239
  68. Verdura S, Cuyas E, Martin-Castillo B and Menendez JA (2019) Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy. Oncoimmunology 8, e1633235 https://doi.org/10.1080/2162402X.2019.1633235
  69. Han Y, Li CW, Hsu JM et al (2019) Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1 upregulation in triple-negative breast cancer. Am J Cancer Res 9, 800-815
  70. Garner H and de Visser KE (2020) Immune crosstalk in cancer progression and metastatic spread: a complex conversation. Nat Rev Immunol 20, 483-497 https://doi.org/10.1038/s41577-019-0271-z
  71. Voss K, Larsen SE and Snow AL (2017) Metabolic reprogramming and apoptosis sensitivity: Defining the contours of a T cell response. Cancer Lett 408, 190-196 https://doi.org/10.1016/j.canlet.2017.08.033
  72. Burns JS and Manda G (2017) Metabolic Pathways of the Warburg Effect in Health and Disease: Perspectives of Choice, Chain or Chance. Int J Mol Sci 18, 2755 https://doi.org/10.3390/ijms18122755
  73. Almeida L, Lochner M, Berod L and Sparwasser T (2016) Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol 28, 514-524 https://doi.org/10.1016/j.smim.2016.10.009
  74. Afonso J, Santos LL, Longatto-Filho A and Baltazar F (2020) Competitive glucose metabolism as a target to boost bladder cancer immunotherapy. Nat Rev Urol 17, 77-106 https://doi.org/10.1038/s41585-019-0263-6
  75. Garza-Lombo C, Schroder A, Reyes-Reyes EM and Franco R (2018) mTOR/AMPK signaling in the brain: Cell metabolism, proteostasis and survival. Curr Opin Toxicol 8, 102-110 https://doi.org/10.1016/j.cotox.2018.05.002
  76. Blagih J, Coulombe F, Vincent EE et al (2015) The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42, 41-54 https://doi.org/10.1016/j.immuni.2014.12.030
  77. Rao E, Zhang Y, Zhu G et al (2015) Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 6, 7944-7958 https://doi.org/10.18632/oncotarget.3501
  78. Pollizzi KN, Patel CH, Sun IH et al (2015) mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J Clin Invest 125, 2090-2108 https://doi.org/10.1172/JCI77746
  79. Pennock ND, White JT, Cross EW, Cheney EE, Tamburini BA and Kedl RM (2013) T cell responses: naive to memory and everything in between. Adv Physiol Educ 37, 273-283 https://doi.org/10.1152/advan.00066.2013
  80. van der Windt GJ and Pearce EL (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249, 27-42 https://doi.org/10.1111/j.1600-065X.2012.01150.x
  81. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B and Cantrell DA (2013) AMPKalpha1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol 43, 889-896 https://doi.org/10.1002/eji.201243008
  82. Araki K, Turner AP, Shaffer VO et al (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108-112 https://doi.org/10.1038/nature08155
  83. Durack J and Lynch SV (2019) The gut microbiome Relationships with disease and opportunities for therapy. J Exp Med 216, 20-40 https://doi.org/10.1084/jem.20180448
  84. Xu H, Liu M, Cao J et al (2019) The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases. J Immunol Res 2019, 7546047
  85. Balakrishnan B and Taneja V (2018) Microbial modulation of the gut microbiome for treating autoimmune diseases. Expert Rev Gastroenterol Hepatol 12, 985-996 https://doi.org/10.1080/17474124.2018.1517044
  86. Gopalakrishnan V, Spencer CN, Nezi L et al (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359, 97-103 https://doi.org/10.1126/science.aan4236
  87. Matson V, Fessler J, Bao R et al (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104-108 https://doi.org/10.1126/science.aao3290
  88. Routy B, Le Chatelier E, Derosa L et al (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359, 91-97 https://doi.org/10.1126/science.aan3706
  89. de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V et al (2017) Metformin Is Associated With Higher Relative Abundance of Mucin-Degrading Akkermansia muciniphila and Several Short-Chain Fatty Acid-Producing Microbiota in the Gut. Diabetes Care 40, 54-62 https://doi.org/10.2337/dc16-1324
  90. Feng W, Ao H and Peng C (2018) Gut Microbiota, Short-Chain Fatty Acids, and Herbal Medicines. Front Pharmacol 9, 1354 https://doi.org/10.3389/fphar.2018.01354
  91. Parada Venegas D, De la Fuente MK, Landskron G et al (2019) Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases. Front Immunol 10, 277 https://doi.org/10.3389/fimmu.2019.00277
  92. Waldman AD, Fritz JM and Lenardo MJ (2020) A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20, 1-18 https://doi.org/10.1038/s41577-019-0258-9
  93. Duan Q, Zhang H, Zheng J and Zhang L (2020) Turning Cold into Hot: Firing up the Tumor Microenvironment. Trends Cancer 6, 605-618 https://doi.org/10.1016/j.trecan.2020.02.022
  94. Bonaventura P, Shekarian T, Alcazer V et al (2019) Cold Tumors: A Therapeutic Challenge for Immunotherapy. Front Immunol 10, 168 https://doi.org/10.3389/fimmu.2019.00168