Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy

References

• Ho PC, Liu PS. Metabolic communication in tumors: a new layer of immunoregulation for immune evasion. J Immunother Cancer. 2016;4:4. doi:10.1186/s40425-016-0109-1.
   PubMed Web of Science ®Google Scholar
• Allison KE, Coomber BL, Bridle BW. Metabolic reprogramming in the tumour microenvironment: a hallmark shared by cancer cells and T lymphocytes. Immunology. 2017;152:175–184. doi:10.1111/imm.12777.
   PubMed Web of Science ®Google Scholar
• Sugiura A, Rathmell JC. Metabolic barriers to T cell function in tumors. J Immunol. 2018;200:400–407. doi:10.4049/jimmunol.1701041.
   PubMed Web of Science ®Google Scholar
• Singer K, Cheng WC, Kreutz M, Ho PC, Siska PJ. Immunometabolism in cancer at a glance. Dis Model Mech. 2018;11(8). pii: dmm034272. doi:10.1242/dmm.034272.
   PubMed Web of Science ®Google Scholar
• Li X, Wenes M, Romero P, Huang SC, Fendt SM, Ho PC. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019 Mar 26. doi: 10.1038/s41571-019-0203-7.
   Web of Science ®Google Scholar
• Renner K, Singer K, Koehl GE, Geissler EK, Peter K, Siska PJ, Kreutz M. Metabolic hallmarks of tumor and immune cells in the tumor microenvironment. Front Immunol. 2017;8:248. doi:10.3389/fimmu.2017.00248.
   PubMed Web of Science ®Google Scholar
• Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 2014;513:559–563. doi:10.1038/nature13490.
   PubMed Web of Science ®Google Scholar
• Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L, Levine MH, Wang Z, Quinn WJ 3rd, Kopinski PK, Wang L, et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab. 2017;25:1282–1293.e7. doi:10.1016/j.cmet.2016.12.018.
   PubMed Web of Science ®Google Scholar
• Bohn T, Rapp S, Luther N, Klein M, Bruehl TJ, Kojima N, Aranda Lopez P, Hahlbrock J, Muth S, Endo S, et al. Tumor immunoevasion via acidosis-dependent induction of regulatory tumor-associated macrophages. Nat Immunol. 2018;19:1319–1329. doi:10.1038/s41590-018-0226-8.
   PubMed Web of Science ®Google Scholar
• Galluzzi L, Kroemer G. Potent immunosuppressive effects of the oncometabolite R-2-hydroxyglutarate. Oncoimmunology. 2018;7:e1528815. doi:10.1080/2162402X.2018.1490854.
   PubMed Web of Science ®Google Scholar
• Yi M, Yu S, Qin S, Liu Q, Xu H, Zhao W, Chu Q, Wu K. Gut microbiome modulates efficacy of immune checkpoint inhibitors. J Hematol Oncol. 2018;11:47. doi:10.1186/s13045-018-0592-6.
   PubMed Web of Science ®Google Scholar
• Lettieri-Barbato D, Aquilano K. Pushing the limits of cancer therapy: the nutrient game. Front Oncol. 2018;8:148. doi:10.3389/fonc.2018.00148.
   PubMed Web of Science ®Google Scholar
• Pollak M. Potential applications for biguanides in oncology. J Clin Invest. 2013;123:3693–3700. doi:10.1172/JCI67232.
   PubMed Web of Science ®Google Scholar
• Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–966. doi:10.1016/j.cmet.2014.09.018.
   PubMed Web of Science ®Google Scholar
• Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging. Cell Metab. 2016;23:1060–1065. doi:10.1016/j.cmet.2016.05.011.
   PubMed Web of Science ®Google Scholar
• Pietrocola F, Kroemer G. Metformin: a metabolic modulator. Oncotarget. 2017;8:9017–9020. doi:10.18632/oncotarget.14794.
   PubMedGoogle Scholar
• Kalender A, Selvaraj A, Kim SY, Gulati P, Brûlé S, Viollet B, Kemp BE, Bardeesy N, Dennis P, Schlager JJ, et al. Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner. Cell Metab. 2010;11:390–401. doi:10.1016/j.cmet.2010.03.014.
   PubMed Web of Science ®Google Scholar
• Wu L, Zhou B, Oshiro-Rapley N, Li M, Paulo JA, Webster CM, Mou F, Kacergis MC, Talkowski ME, Carr CE, et al. Unified mechanism for metformin growth inhibition in C. elegans and cancer. Cell. 2016;167:1705–1718.e13. doi:10.1016/j.cell.2016.11.055.
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Fernández-Arroyo S, Joven J, Menendez JA. Metformin targets histone acetylation in cancer-prone epithelial cells. Cell Cycle. 2016;15:3355–3361. doi:10.1080/15384101.2016.1249547.
   PubMed Web of Science ®Google Scholar
• Bridgeman SC, Ellison GC, Melton PE, Newsholme P, Mamotte CDS. Epigenetic effects of metformin: from molecular mechanisms to clinical implications. Diabetes Obes Metab. 2018;20:1553–1562. doi:10.1111/dom.13262.
   PubMed Web of Science ®Google Scholar
• Blank CU, Haanen JB, Ribas A, Schumacher TN. CANCER IMMUNOLOGY. The “cancer immunogram”. Science. 2016;352:658–660. doi:10.1126/science.aaf2834.
   PubMed Web of Science ®Google Scholar
• Hirsch HA, Iliopoulos D, Struhl K. Metformin inhibits the inflammatory response associated with cellular transformation and cancerstem cell growth. Proc Natl Acad Sci U S A. 2013;110:972–977. doi:10.1073/pnas.1221055110.
   PubMed Web of Science ®Google Scholar
• Al-Wahab Z, Mert I, Tebbe C, Chhina J, Hijaz M, Morris RT, Ali-Fehmi R, Giri S, Munkarah AR, Rattan R. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction. Oncotarget. 2015;6:10908–10923. doi:10.18632/oncotarget.3434.
   PubMedGoogle Scholar
• Xu S, Yang Z, Jin P, Yang X, Li X, Wei X, Wang Y, Long S, Zhang T, Chen G, et al. Metformin suppresses tumor progression by inactivating stromal fibroblasts in ovarian cancer. Mol Cancer Ther. 2018;17:1291–1302. doi:10.1158/1535-7163.MCT-17-0927.
   PubMed Web of Science ®Google Scholar
• Oliveras-Ferraros C, Cufí S, Vazquez-Martin A, Menendez OJ, Bosch-Barrera J, Martin-Castillo B, Joven J, Menendez JA. Metformin rescues cell surface major histocompatibility complex class I (MHC-I) deficiency caused by oncogenic transformation. Cell Cycle. 2012;11:865–870. doi:10.4161/cc.11.5.19252.
   PubMed Web of Science ®Google Scholar
• Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cochemé HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D. Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell. 2013;153:228–239. doi:10.1016/j.cell.2013.02.035.
   PubMed Web of Science ®Google Scholar
• Corominas-Faja B, Quirantes-Piné R, Oliveras-Ferraros C, Vazquez-Martin A, Cufí S, Martin-Castillo B, Micol V, Joven J, Segura-Carretero A, Menendez JA. Metabolomic fingerprint reveals that metformin impairs one-carbon metabolism in a manner similar to the antifolate class of chemotherapy drugs. Aging (Albany NY). 2012;4:480–498. doi:10.18632/aging.100472.
   PubMedGoogle Scholar
• Cuyàs E, Fernández-Arroyo S, Verdura S, García RÁ, Stursa J, Werner L, Blanco-González E, Montes-Bayón M, Joven J, Viollet B, et al. Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene. 2018;37:963–970. doi:10.1038/onc.2017.367.
   PubMed Web of Science ®Google Scholar
• Cuyàs E, Fernández-Arroyo S, Buxó M, Pernas S, Dorca J, Álvarez I, Martínez S, Pérez-Garcia JM, Batista-López N, Rodríguez-Sánchez CA, et al. Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients. Aging (Albany NY). 2019;11:2874–2888. doi:10.18632/aging.101960.
   PubMedGoogle Scholar
• Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature. 2009;460:103–107. doi:10.1038/nature08097.
   PubMed Web of Science ®Google Scholar
• Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R. mTOR regulates memory CD8 T-cell differentiation. Nature. 2009;460:108–112. doi:10.1038/nature08155.
   PubMed Web of Science ®Google Scholar
• Prlic M, Bevan MJ. Immunology: A metabolic switch to memory. Nature. 2009;460:41–42. doi:10.1038/460041a.
   PubMed Web of Science ®Google Scholar
• Wherry EJ. T cell exhaustion. Nat Immunol. 2011;12:492–499.
   PubMed Web of Science ®Google Scholar
• Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8:793–800. doi:10.1038/nm730.
   PubMed Web of Science ®Google Scholar
• Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64:1140–1145.
   PubMed Web of Science ®Google Scholar
• Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A. 2002;99:12293–12297. doi:10.1073/pnas.192461099.
   PubMed Web of Science ®Google Scholar
• Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A. 2015;112:1809–1814. doi:10.1073/pnas.1417636112.
   PubMed Web of Science ®Google Scholar
• Araki K, Youngblood B, Ahmed R. The role of mTOR in memory CD8 T-cell differentiation. Immunol Rev. 2010;235:234–243. doi:10.1111/j.0105-2896.2010.00898.x.
   PubMed Web of Science ®Google Scholar
• Pereira FV, Melo ACL, Low JS, de Castro ÍA, Braga TT, Almeida DC, Batista de Lima AGU, Hiyane MI, Correa-Costa M, Andrade-Oliveira V, et al. Metformin exerts antitumor activity via induction of multiple death pathways in tumor cells and activation of a protective immune response. Oncotarget. 2018;9:25808–25825. doi:10.18632/oncotarget.25380.
   PubMedGoogle Scholar
• Church SE, Jensen SM, Antony PA, Restifo NP, Fox BA. Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells. Eur J Immunol. 2014;44:69–79. doi:10.1002/eji.201343718.
   PubMed Web of Science ®Google Scholar
• Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, et al. Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol. 2015;16:871–879. doi:10.1038/ni.3224.
   PubMed Web of Science ®Google Scholar
• Ding L, Liang G, Yao Z, Zhang J, Liu R, Chen H, Zhou Y, Wu H, Yang B, He Q. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015;6:36441–36455. doi:10.18632/oncotarget.v6i34.
   PubMedGoogle Scholar
• Munipally PK, Agraharm SG, Valavala VK, Gundae S, Turlapati NR. Evaluation of indoleamine 2,3-dioxygenase expression and kynurenine pathway metabolites levels in serum samples of diabetic retinopathy patients. Arch Physiol Biochem. 2011;117:254–258. doi:10.3109/13813455.2011.623705.
   PubMed Web of Science ®Google Scholar
• Muzik O, Burghardt P, Yi Z, Kumar A, Seyoum B. Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway. Biochem Biophys Res Commun. 2017;488:29–32. doi:10.1016/j.bbrc.2017.04.155.
   PubMed Web of Science ®Google Scholar
• Uehara T, Eikawa S, Nishida M, Kunisada Y, Yoshida A, Fujiwara T, Kunisada T, Ozaki T, Udono H. Metformin induces CD11b+ cell-mediated growth inhibition of an osteosarcoma: implications for metabolic reprogramming of myeloid cells and antitumor effects. Int Immunol. 2018 Dec 2. doi:10.1093/intimm/dxy079. [Epub ahead of print].
   Web of Science ®Google Scholar
• Kunisada Y, Eikawa S, Tomonobu N, Domae S, Uehara T, Hori S, Furusawa Y, Hase K, Sasaki A, Udono H. Attenuation of CD4+CD25+ regulatory T cells in the tumor microenvironment by metformin, a type 2 diabetes drug. EBioMedicine. 2017;25:154–164. doi:10.1016/j.ebiom.2017.10.009.
   PubMed Web of Science ®Google Scholar
• Walker LS. Treg and CTLA-4: two intertwining pathways to immune tolerance. J Autoimmun. 2013;45:49–57. doi:10.1016/j.jaut.2013.06.006.
   PubMed Web of Science ®Google Scholar
• Walker LS, Sansom DM. Confusing signals: recent progress in CTLA-4 biology. Trends Immunol. 2015;36:63–70. doi:10.1016/j.it.2014.12.001.
   PubMed Web of Science ®Google Scholar
• Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, et al. Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 2014 May 12;25(5):590–604. doi:10.1016/j.ccr.2014.03.033.
   PubMed Web of Science ®Google Scholar
• Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, Gouw AM, Baylot V, Gütgemann I, Eilers M, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016 Apr 8;352(6282):227–231. doi:10.1126/science.aac9935.
   PubMed Web of Science ®Google Scholar
• Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA, et al. Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008 Dec 30;105(52):20852–20857. doi:10.1073/pnas.0810958105.
   PubMed Web of Science ®Google Scholar
• Lastwika KJ, Wilson W 3rd, Li QK, Norris J, Xu H, Ghazarian SR, Kitagawa H, Kawabata S, Taube JM, Yao S, et al. Control of PD-L1 expression by oncogenic activation of the AKT-mTOR pathway in non-small cell lung cancer. Cancer Res. 2016;76:227–238. doi:10.1158/0008-5472.CAN-14-3362.
   PubMed Web of Science ®Google Scholar
• Ho Y, Chen YF, Wang LH, Hsu KY, Chin YT, Yang YSH, Wang SH, Chen YR, Shih YJ, Liu LF, et al. Inhibitory effect of anoectochilus formosanus extract on hyperglycemia-related PD-L1 expression and cancer proliferation. Front Pharmacol. 2018;9:807. doi:10.3389/fphar.2018.00807.
   PubMed Web of Science ®Google Scholar
• Cha JH, Yang WH, Xia W, Wei Y, Chan LC, Lim SO, Li CW, Kim T, Chang SS, Lee HH, et al. Metformin promotes antitumor immunity via endoplasmic-reticulim-associated degradation of PD-L1. Mol Cell. 2018;71:606–620.e7. doi:10.1016/j.molcel.2018.07.030.
   PubMed Web of Science ®Google Scholar
• Dreher LS, Hoppe T. ERADicate tumor progression with metformin. Mol Cell. 2018;71:481–482. doi:10.1016/j.molcel.2018.08.001.
   PubMed Web of Science ®Google Scholar
• Rom-Jurek EM, Kirchhammer N, Ugocsai P, Ortmann O, Wege AK, Brockhoff G. Regulation of programmed death ligand 1 (PD-L1) expression in breast cancer cell lines in vitro and in immunodeficient and humanized tumor mice. Int J Mol Sci. 2018;19. pii: E563. doi:10.3390/ijms19020563.
   PubMed Web of Science ®Google Scholar
• Henle AM, Erskine CL, Benson LM, Clynes R, Knutson KL. Enzymatic discovery of a HER-2/neu epitope that generates cross-reactive T cells. J Immunol. 2013;190:479–488. doi:10.4049/jimmunol.1201264.
   PubMed Web of Science ®Google Scholar
• Erskine CL, Henle AM, Knutson KL. Determining optimal cytotoxic activity of human Her2neu specific CD8 T cells by comparing the Cr51 release assay to the xCELLigence system. J Vis Exp. 2012;66:e3683. doi:10.3791/3683.
   PubMed Web of Science ®Google Scholar
• Mandai M, Hamanishi J, Abiko K, Matsumura N, Baba T, Konishi I. Dual faces of ifnγ in cancer progression: a role of PD-L1 induction in the determination of pro- and antitumor immunity. Clin Cancer Res. 2016;22:2329–2334. doi:10.1158/1078-0432.CCR-16-0224.
   PubMed Web of Science ®Google Scholar
• Mezzadra R, Sun C, Jae LT, Gomez-Eerland R, de Vries E, Wu W, Logtenberg MEW, Slagter M, Rozeman EA, Hofland I, et al. Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature. 2017;549:106–110. doi:10.1038/nature23669.
   PubMed Web of Science ®Google Scholar
• Han Y, Li CW, Hsu JM, Hsu JL, Chan LC, Tan X, He GJ. Metformin reverses PARP inhibitors-induced epithelial-mesenchymal transition and PD-L1upregulation in triple-negative breast cancer. Am J Cancer Res. 2019;9:800–815.
   PubMed Web of Science ®Google Scholar
• Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, et al. Aberrant PD-L1 expression through 3ʹ-UTR disruption in multiple cancers. Nature. 2016;534:402–406. doi:10.1038/nature18294.
   PubMed Web of Science ®Google Scholar
• Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, Freeman GJ, Krogsgaard M, Riley JL. Strength of PD-1 signaling differentially affects T-cell effector functions. Proc Natl Acad Sci U S A. 2013;110:E2480–9. doi:10.1073/pnas.1305394110.
   PubMed Web of Science ®Google Scholar
• Zitvogel L, Galluzzi L, Viaud S, Vétizou M, Daillère R, Merad M, Kroemer G. Cancer and the gut microbiota: an unexpected link. Sci Transl Med. 2015;7:271ps1. doi:10.1126/scitranslmed.aad3106.
   PubMed Web of Science ®Google Scholar
• Brennan CA, Garrett WS. Gut microbiota, inflammation, and colorectal cancer. Annu Rev Microbiol. 2016;70:395–411. doi:10.1146/annurev-micro-102215-095513.
   PubMed Web of Science ®Google Scholar
• Routy B, Gopalakrishnan V, Daillère R, Zitvogel L, Wargo JA, Kroemer G. The gut microbiota influences anticancer immunosurveillance and general health. Nat Rev Clin Oncol. 2018;15:382–396. doi:10.1038/s41571-018-0006-2.
   PubMed Web of Science ®Google Scholar
• Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017;17:271–285. doi:10.1038/nrc.2017.13.
   PubMed Web of Science ®Google Scholar
• Alexander JL, Wilson ID, Teare J, Marchesi JR, Nicholson JK, Kinross JM. Gut microbiota modulation of chemotherapy efficacy and toxicity. Nat Rev Gastroenterol Hepatol. 2017;14:356–365. doi:10.1038/nrgastro.2017.20.
   PubMed Web of Science ®Google Scholar
• Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1079–1084. doi:10.1126/science.aad1329.
   PubMed Web of Science ®Google Scholar
• Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103. doi:10.1126/science.aan4236.
   PubMed Web of Science ®Google Scholar
• Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–108. doi:10.1126/science.aao3290.
   PubMed Web of Science ®Google Scholar
• Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–97. doi:10.1126/science.aan3706.
   PubMed Web of Science ®Google Scholar
• Chaput N, Lepage P, Coutzac C, Soularue E, Le Roux K, Monot C, Boselli L, Routier E, Cassard L, Collins M, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28:1368–1379. doi:10.1093/annonc/mdx108.
   PubMed Web of Science ®Google Scholar
• Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, Prifti E, Vieira-Silva S, Gudmundsdottir V, Pedersen HK, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature. 2015;528:262–266. doi:10.1038/nature15766.
   PubMed Web of Science ®Google Scholar
• Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med. 2017;23:850–858. doi:10.1038/nm.4345.
   PubMed Web of Science ®Google Scholar
• Pollak M. The effects of metformin on gut microbiota and the immune system as research frontiers. Diabetologia. 2017;60:1662–1667. doi:10.1007/s00125-017-4352-x.
   PubMed Web of Science ®Google Scholar
• de la Cuesta-Zuluaga J, Mueller NT, Corrales-Agudelo V, Velásquez-Mejía EP, Carmona JA, Abad JM, Escobar JS. 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. 2017;40:54–62. doi:10.2337/dc16-1324.
   PubMed Web of Science ®Google Scholar
• Lee H, Lee Y, Kim J, An J, Lee S, Kong H, Song Y, Lee CK, Kim K. Modulation of the gut microbiota by metformin improves metabolic profiles in aged obese mice. Gut Microbes. 2018;9:155–165. doi:10.1080/19490976.2017.1405209.
   PubMed Web of Science ®Google Scholar
• Kyriachenko Y, Falalyeyeva T, Korotkyi O, Molochek N, Kobyliak N. Crosstalk between gut microbiota and antidiabetic drug action. World J Diabetes. 2019;10:154–168. doi:10.4239/wjd.v10.i3.154.
   PubMed Web of Science ®Google Scholar
• Shin NR, Lee JC, Lee HY, Kim MS, Whon TW, Lee MS, Bae JW. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014;63:727–735. doi:10.1136/gutjnl-2012-303839.
   PubMed Web of Science ®Google Scholar
• Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013;504:446–450. doi:10.1038/nature12721.
   PubMed Web of Science ®Google Scholar
• Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-Y M, Glickman JN, Garrett WS. The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science. 2013;341:569–573. doi:10.1126/science.1241165.
   PubMed Web of Science ®Google Scholar
• Schuler KM, Rambally BS, DiFurio MJ, Sampey BP, Gehrig PA, Makowski L, Bae-Jump VL. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer. Cancer Med. 2015;4:161–173. doi:10.1002/cam4.353.
   PubMed Web of Science ®Google Scholar
• Scharping NE, Menk AV, Whetstone RD, Zeng X, Delgoffe GM. Efficacy of PD-1 blockade is potentiated by metformin-induced reduction of tumor hypoxia. Cancer Immunol Res. 2017;5:9–16. doi:10.1158/2326-6066.CIR-16-0103.
   PubMed Web of Science ®Google Scholar
• Haikala HM, Anttila JM, Marques E, Raatikainen T, Ilander M, Hakanen H, Ala-Hongisto H, Savelius M, Balboa D, Von Eyss B, et al. Pharmacological reactivation of MYC-dependent apoptosis induces susceptibility to anti-PD-1 immunotherapy. Nat Commun. 2019;10:620. doi:10.1038/s41467-019-08541-2.
   PubMed Web of Science ®Google Scholar
• Afzal MZ, Mercado RR, Shirai K. Efficacy of metformin in combination with immune checkpoint inhibitors (anti-PD-1/anti-CTLA-4) in metastatic malignant melanoma. J Immunother Cancer. 2018;6:64. doi:10.1186/s40425-018-0375-1.
   PubMed Web of Science ®Google Scholar
• Curry JM, Johnson J, Mollaee M, Tassone P, Amin D, Knops A, Whitaker-Menezes D, Mahoney MG, South A, Rodeck U, et al. Metformin clinical trial in HPV+ and HPV- head and neck squamous cell carcinoma: impact on cancer cell apoptosis and immune infiltrate. Front Oncol. 2018;8:436. doi:10.3389/fonc.2018.00436.
   PubMed Web of Science ®Google Scholar
• Pietras H, Xu H, Hu X, Matheny C, Sandler A, Patel M. P1.04-33 retrospective descriptive analysis of metformin with atezolizumab in advanced non-small cell lung cancer in the OAK trial. J Thorac Oncol. 2018;13:S538–S539. doi:10.1016/j.jtho.2018.08.748.
   Web of Science ®Google Scholar
• Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H, Kiura K. Study protocol: phase-ib trial of nivolumab combined with metformin for refractory/recurrent solid tumors. Clin Lung Cancer. 2018;19:e861–e864. doi:10.1016/j.cllc.2018.07.010.
   PubMed Web of Science ®Google Scholar
• Zhou H, Liu J, Zhang Y, Zhang L. Inflammatory bowel disease associated with the combination treatment of nivolumab and metformin: data from the FDA adverse event reporting system. Cancer Chemother Pharmacol. 2019;83:599–601. doi:10.1007/s00280-018-03763-5.
   PubMed Web of Science ®Google Scholar
• Rogado J, Sánchez-Torres JM, Romero-Laorden N, Ballesteros AI, Pacheco-Barcia V, Ramos-Leví A, Arranz R, Lorenzo A, Gullón P, Donnay O, et al. Immune-related adverse events predict the therapeutic efficacy of anti-PD-1 antibodies in cancer patients. Eur J Cancer. 2019;109:21–27. doi:10.1016/j.ejca.2018.10.014.
   PubMed Web of Science ®Google Scholar
• Changizzadeh PN, Mukkamalla SKR, Armenio VA. Combined checkpoint inhibitor therapy causing diabetic ketoacidosis in metastatic melanoma. J Immunother Cancer. 2017;5:97. doi:10.1186/s40425-017-0303-9.
   PubMed Web of Science ®Google Scholar
• Gauci ML, Laly P, Vidal-Trecan T, Baroudjian B, Gottlieb J, Madjlessi-Ezra N, Da Meda L, Madelaine-Chambrin I, Bagot M, Basset-Seguin N, et al. Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review. Cancer Immunol Immunother. 2017;66:1399–1410. doi:10.1007/s00262-017-2033-8.
   PubMed Web of Science ®Google Scholar
• Godwin JL, Jaggi S, Sirisena I, Sharda P, Rao AD, Mehra R, Veloski C. Nivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer. J Immunother Cancer. 2017;5:40. doi:10.1186/s40425-017-0245-2.
   PubMed Web of Science ®Google Scholar
• Maamari J, Yeung SJ, Chaftari PS. Diabetic ketoacidosis induced by a single dose of pembrolizumab. Am J Emerg Med. 2019;37:376.e1–376.e2. doi:10.1016/j.ajem.2018.10.040.
   PubMed Web of Science ®Google Scholar
• Wang Y, Wang H, Yao H, Li C, Fang JY, Xu J. Regulation of PD-L1: emerging routes for targeting tumor immune evasion. Front Pharmacol. 2018;9:536. doi:10.3389/fphar.2018.00536.
   PubMed Web of Science ®Google Scholar
• Gu W, Wang L, Wu Y, Liu JP. Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD-1/PD-L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells. Clin Exp Pharmacol Physiol. 2019;46:105–115. doi:10.1111/1440-1681.13056.
   PubMed Web of Science ®Google Scholar
• Del Barco S, Vazquez-Martin A, Cufí S, Oliveras-Ferraros C, Bosch-Barrera J, Joven J, Martin-Castillo B, Menendez JA. Metformin: multi-faceted protection against cancer. Oncotarget. 2011;2:896–917. doi:10.18632/oncotarget.387.
   PubMed Web of Science ®Google Scholar
• Decensi A, Puntoni M, Goodwin P, Cazzaniga M, Gennari A, Bonanni B, Gandini S. Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2010;3:1451–1461. doi:10.1158/1940-6207.CAPR-10-0157.
   PubMed Web of Science ®Google Scholar
• Col NF, Ochs L, Springmann V, Aragaki AK, Chlebowski RT. Metformin and breast cancer risk: a meta-analysis and critical literature review. Breast Cancer Res Treat. 2012;135:639–646. doi:10.1007/s10549-012-2170-x.
   PubMed Web of Science ®Google Scholar
• Goodwin PJ, Stambolic V, Lemieux J, Chen BE, Parulekar WR, Gelmon KA, Hershman DL, Hobday TJ, Ligibel JA, Mayer IA, et al. Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents. Breast Cancer Res Treat. 2011;126:215–220. doi:10.1007/s10549-010-1224-1.
   PubMed Web of Science ®Google Scholar
• Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012;2:778–790. doi:10.1158/2159-8290.CD-12-0263.
   PubMed Web of Science ®Google Scholar
• Kordes S, Pollak MN, Zwinderman AH, Mathôt RA, Weterman MJ, Beeker A, Punt CJ, Richel DJ, Wilmink JW. Metformin in patients with advanced pancreatic cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol. 2015;16:839–847. doi:10.1016/S1470-2045(15)00027-3.
   PubMed Web of Science ®Google Scholar
• Reni M, Dugnani E, Cereda S, Belli C, Balzano G, Nicoletti R, Liberati D, Pasquale V, Scavini M, Maggiora P, et al. (Ir)relevance of metformin treatment in patients with metastatic pancreatic cancer: an open-label, randomized phase II trial. Clin Cancer Res. 2016;22:1076–1085. doi:10.1158/1078-0432.CCR-16-0190.
   PubMed Web of Science ®Google Scholar
• Martin-Castillo B, Pernas S, Dorca J, Álvarez I, Martínez S, Pérez-Garcia JM, Batista-López N, Rodríguez-Sánchez CA, Amillano K, Domínguez S, et al. A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study. Oncotarget. 2018;9:35687–35704. doi:10.18632/oncotarget.26286.
   PubMedGoogle Scholar
• Chae YK, Oh MS, Giles FJ. Molecular biomarkers of primary and acquired resistance to T-cell-mediated immunotherapy in cancer: landscape, clinical implications, and future directions. Oncologist. 2018;23:410–421. doi:10.1634/theoncologist.2017-0354.
   PubMed Web of Science ®Google Scholar
• Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, Mirsoian A, Minnar CM, Stoffel KM, Sturgill IR, et al. Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nat Med. 2019;25:141–151. doi:10.1038/s41591-018-0221-5.
   PubMed Web of Science ®Google Scholar
• Cortellini A, Bersanelli M, Buti S, Cannita K, Santini D, Perrone F, Giusti R, Tiseo M, Michiara M, Di Marino P, et al. A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. J Immunother Cancer. 2019;7:57. doi:10.1186/s40425-019-0527-y.
   PubMed Web of Science ®Google Scholar
• Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth 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. doi:10.1038/ncomms7692.
   PubMed Web of Science ®Google Scholar
• Qorraj M, Böttcher M, Mougiakakos D. PD-L1/PD-1: new kid on the “immune metabolic” block. Oncotarget. 2017;8:73364–73365. doi:10.18632/oncotarget.20639.
   PubMedGoogle Scholar
• Bonanni B, Puntoni M, Cazzaniga M, Pruneri G, Serrano D, Guerrieri-Gonzaga A, Gennari A, Trabacca MS, Galimberti V, Veronesi P, et al. Dual effect of metformin on breast cancer proliferation in a randomized presurgical trial. J Clin Oncol. 2012;30:2593–2600. doi:10.1200/JCO.2011.39.3769.
   PubMed Web of Science ®Google Scholar
• DeCensi A, Puntoni M, Gandini S, Guerrieri-Gonzaga A, Johansson HA, Cazzaniga M, Pruneri G, Serrano D, Schwab M, Hofmann U, et al. Differential effects of metformin on breast cancer proliferation according to markers of insulin resistance and tumor subtype in a randomized presurgical trial. Breast Cancer Res Treat. 2014;148:81–90. doi:10.1007/s10549-014-3141-1.
   PubMed Web of Science ®Google Scholar
• Spencer CN, Wells DK, LaVallee TM. It is a capital mistake to theorize who to treat with checkpoint inhibitors before one has data. Trends Cancer. 2019;5:79–82. doi:10.1016/j.trecan.2018.12.003.
   PubMed Web of Science ®Google Scholar
• Karasaki T, Nagayama K, Kuwano H, Nitadori JI, Sato M, Anraku M, Hosoi A, Matsushita H, Morishita Y, Kashiwabara K, et al. An immunogram for the cancer-immunity cycle: towards personalized immunotherapy of lungCancer. J Thorac Oncol. 2017;12:791–803. doi:10.1016/j.jtho.2017.01.005.
   PubMed Web of Science ®Google Scholar
• Zahoor H, Grivas P. The cancer immunogram: a pledge for a comprehensive biomarker approach for personalized immunotherapy in urothelial cancer. Eur Urol. 2019;75:445–447. doi:10.1016/j.eururo.2018.12.005.
   PubMed Web of Science ®Google Scholar
• van Dijk N, Funt SA, Blank CU, Powles T, Rosenberg JE, van der Heijden MS. The cancer immunogram as a framework for personalized immunotherapy in urothelial cancer. Eur Urol. 2019;75:435–444. doi:10.1016/j.eururo.2018.09.022.
   PubMed Web of Science ®Google Scholar
• Tarantino P, Curigliano G. Defining the immunogram of breast cancer: a focus on clinical trials. Expert Opin Biol Ther. 2019;19:383–385. doi:10.1080/14712598.2019.1598372.
   PubMed Web of Science ®Google Scholar