Abstract
BCG is widely used for cancer treatment, where macrophages play an important role. However, the mechanism of BCG affecting macrophages remains poorly understood. In this study, we used BCG to stimulate myeloid-derived macrophages lacking HIF-1α, the levels of TNF-α, IL-1β, CD86 of macrophages and their effects on the growth of tumor cells MCA207 and B16-F10 were detected. We found that the absence of HIF-1α prevents BCG-stimulated macrophages from polarizing towards the M (BCG) and attenuating its killing effect on tumor cells. In addition, we demonstrated that the tumors of mice lacking HIF-1α in macrophages were significantly increased by the experiment of mice transplantation. Our study provides relevant evidence for exploring the mechanism of the BCG vaccine in the prevention and treatment of related diseases.
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References
Old LJ, Clarke DA, Benacerraf B (1959) Effect of bacillus Calmette-Guerin infection on transplanted tumours in the mouse. Nature 184(5):291–292. https://doi.org/10.1038/184291a0
Dobosz P, Dzieciątkowski T (2019) The intriguing history of cancer immunotherapy. Front Immunol 10:2965. https://doi.org/10.3389/fimmu.2019.02965
Morales A, Eidinger D, Bruce AW (1976) Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 116(2):180–183. https://doi.org/10.1016/s0022-5347(17)58737-6
Sloot S, Rashid OM, Sarnaik AA, Zager JS (2016) Developments in intralesional therapy for metastatic melanoma. Cancer Control: J Moffitt Cancer Center 23(1):12–20. https://doi.org/10.1177/107327481602300104
Taniguchi K, Koga S, Nishikido M, Yamashita S, Sakuragi T, Kanetake H, Saito Y (1999) Systemic immune response after intravesical instillation of bacille Calmette-Guérin (BCG) for superficial bladder cancer. Clin Exp Immunol 115(1):131–135. https://doi.org/10.1046/j.1365-2249.1999.00756.x
Siracusano S, Vita F, Abbate R, Ciciliato S, Borelli V, Bernabei M, Zabucchi G (2007) The role of granulocytes following intravesical BCG prophylaxis. Eur Urol 51(6):1589–1597. https://doi.org/10.1016/j.eururo.2006.11.045 (discussion 1597–1589)
Brandau S, Suttmann H, Riemensberger J, Seitzer U, Arnold J, Durek C, Jocham D, Flad HD, Böhle A (2000) Perforin-mediated lysis of tumor cells by mycobacterium bovis bacillus Calmette-Guérin-activated killer cells. Clin Cancer Res: Off J Am Assoc Cancer Res 6(9):3729–3738
De Boer E, De Jong W, Van Der Meijden A, Steerenberg P, Witjes J, Vegt P, Debruyne F, Ruitenberg EJCI (1991) Presence of activated lymphocytes in the urine of patients with superficial bladder cancer after intravesical immunotherapy with bacillus Calmette-Guérin. Immunotherapy 33(6):411–416
Juhas U, Ryba-Stanisławowska M, Szargiej P, Myśliwska J (2015) Different pathways of macrophage activation and polarization. Postepy Hig Med Dosw (Online) 69:496–502. https://doi.org/10.5604/17322693.1150133
Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M, Mantovani A, Martinez FO, Mege JL, Mosser DM, Natoli G, Saeij JP, Schultze JL, Shirey KA, Sica A, Suttles J, Udalova I, van Ginderachter JA, Vogel SN, Wynn TA (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41(1):14–20. https://doi.org/10.1016/j.immuni.2014.06.008
Fujisaka S, Usui I, Ikutani M, Aminuddin A, Takikawa A, Tsuneyama K, Mahmood A, Goda N, Nagai Y, Takatsu K, Tobe K (2013) Adipose tissue hypoxia induces inflammatory M1 polarity of macrophages in an HIF-1α-dependent and HIF-1α-independent manner in obese mice. Diabetologia 56(6):1403–1412. https://doi.org/10.1007/s00125-013-2885-1
Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, Tsuneyama K, Nagai Y, Takatsu K, Urakaze M, Kobayashi M, Tobe K (2009) Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes 58(11):2574–2582. https://doi.org/10.2337/db08-1475
Benoit M, Desnues B, Mege JL (2008) Macrophage polarization in bacterial infections. J of Immunology (Baltimore, Md: 1950) 181(6):3733–3739. https://doi.org/10.4049/jimmunol.181.6.3733
Murray PJ (2017) Macrophage polarization. Annu Rev Physiol 79:541–566. https://doi.org/10.1146/annurev-physiol-022516-034339
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, Seifi B, Mohammadi A, Afshari JT, Sahebkar A (2018) Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol 233(9):6425–6440. https://doi.org/10.1002/jcp.26429
Biswas SK, Chittezhath M, Shalova IN, Lim JY (2012) Macrophage polarization and plasticity in health and disease. Immunol Res 53(1–3):11–24. https://doi.org/10.1007/s12026-012-8291-9
Chistiakov DA, Bobryshev YV, Nikiforov NG, Elizova NV, Sobenin IA, Orekhov AN (2015) Macrophage phenotypic plasticity in atherosclerosis: The associated features and the peculiarities of the expression of inflammatory genes. Int J Cardiol 184:436–445. https://doi.org/10.1016/j.ijcard.2015.03.055
Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P (2017) Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol 14(7):399–416. https://doi.org/10.1038/nrclinonc.2016.217
Decker T, Lohmann-Matthes ML, Gifford GE (1987) Cell-associated tumor necrosis factor (TNF) as a killing mechanism of activated cytotoxic macrophages. J of Immunology (Baltimore, Md: 1950) 138(3):957–962
Zhang L, Zhu H, Lun Y, Yan D, Yu L, Du B, Zhu X (2007) Proteomic analysis of macrophages: a potential way to identify novel proteins associated with activation of macrophages for tumor cell killing. Cell Mol Immunol 4(5):359–367
Klimp AH, de Vries EG, Scherphof GL, Daemen T (2002) A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol 44(2):143–161. https://doi.org/10.1016/s1040-8428(01)00203-7
Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL, Lopez-Rosas A, Zhang P, Panek WK, Cordero A, Han Y, Ahmed AU, Chandel NS, Lesniak MS (2019) HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of tregs in glioblastoma. Cell Rep 27(1):226-237.e224. https://doi.org/10.1016/j.celrep.2019.03.029
Donnelly RP, Finlay DK (2015) Glucose, glycolysis and lymphocyte responses. Mol Immunol 68(2 Pt C):513–519. https://doi.org/10.1016/j.molimm.2015.07.034
O’Neill LA, Pearce EJ (2016) Immunometabolism governs dendritic cell and macrophage function. J Exp Med 213(1):15–23. https://doi.org/10.1084/jem.20151570
Corcoran SE, O’Neill LA (2016) HIF1α and metabolic reprogramming in inflammation. J Clin Investig 126(10):3699–3707. https://doi.org/10.1172/jci84431
Cramer T, Yamanishi Y, Clausen BE, Förster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657. https://doi.org/10.1016/s0092-8674(03)00154-5
Stothers CL, Luan L, Fensterheim BA, Bohannon JK (2018) Hypoxia-inducible factor-1α regulation of myeloid cells. J Mol Med (Berl) 96(12):1293–1306. https://doi.org/10.1007/s00109-018-1710-1
Galván-Peña S, O’Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5:420. https://doi.org/10.3389/fimmu.2014.00420
Ding D, Zhu M, Liu X, Jiang L, Xu J, Chen L, Liang J, Li L, Zhou T, Wang Y, Shi H, Yuan Y, Song E (2018) Inhibition of TRAF6 alleviates choroidal neovascularization in vivo. Biochem Biophys Res Commun 503(4):2742–2748. https://doi.org/10.1016/j.bbrc.2018.08.034
Masoud GN, Li W (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta pharmaceutica Sinica B 5(5):378–389. https://doi.org/10.1016/j.apsb.2015.05.007
Kumar P, Tyagi R, Das G, Bhaskar S (2014) Mycobacterium indicus pranii and Mycobacterium bovis BCG lead to differential macrophage activation in Toll-like receptor-dependent manner. Immunology 143(2):258–268. https://doi.org/10.1111/imm.12306
Zhao X, Liu Q, Du B, Li P, Cui Q, Han X, Du B, Yan D, Zhu X (2012) A novel accessory molecule Trim59 involved in cytotoxicity of BCG-activated macrophages. Mol Cells 34(3):263–270. https://doi.org/10.1007/s10059-012-0089-z
Liu Q, Tian Y, Zhao X, Jing H, Xie Q, Li P, Li D, Yan D, Zhu X (2015) NMAAP1 expressed in BCG-activated macrophage promotes M1 macrophage polarization. Mol Cells 38(10):886–894. https://doi.org/10.14348/molcells.2015.0125
Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA, Avizonis D, DeBerardinis RJ, Siegel PM, Jones RG (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124. https://doi.org/10.1016/j.cmet.2012.12.001
Wu Y, Sarkissyan M, McGhee E, Lee S, Vadgama JV (2015) Combined inhibition of glycolysis and AMPK induces synergistic breast cancer cell killing. Breast Cancer Res Treat 151(3):529–539. https://doi.org/10.1007/s10549-015-3386-3
Semba H, Takeda N, Isagawa T, Sugiura Y, Honda K, Wake M, Miyazawa H, Yamaguchi Y, Miura M, Jenkins DM, Choi H, Kim JW, Asagiri M, Cowburn AS, Abe H, Soma K, Koyama K, Katoh M, Sayama K, Goda N, Johnson RS, Manabe I, Nagai R, Komuro I (2016) HIF-1α-PDK1 axis-induced active glycolysis plays an essential role in macrophage migratory capacity. Nat Commun 7:11635. https://doi.org/10.1038/ncomms11635
Guan F, Lu XJ, Li CH, Chen J (2017) Molecular characterization of mudskipper (Boleophthalmus pectinirostris) hypoxia-inducible factor-1α (HIF-1α) and analysis of its function in monocytes/macrophages. PLoS ONE 12(5):e0177960. https://doi.org/10.1371/journal.pone.0177960
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Nos. 81871245) and Department of Education of Jilin Province (JJKH20190095KJ) and the Fundamental Research Funds for the Central Universities of China. The authors appreciate Dr. Zhinan Yin (The Biomedical Translational Research Institute, Jinan University, Guangzhou 510632 Guangdong, PR China) for providing the HIF-1α cKO mice.
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Zhu, P., Hou, Y., Tang, M. et al. The role of HIF-1α in BCG-stimulated macrophages polarization and their tumoricidal effects in vitro. Med Microbiol Immunol 210, 149–156 (2021). https://doi.org/10.1007/s00430-021-00708-3
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DOI: https://doi.org/10.1007/s00430-021-00708-3