Bacteria forming the resident microbiome of the tumor are an integral component of its microenvironment. The interaction of the tumor microbiome with the tumor or tumor stromal cells is not well understood. We hypothesized that bacteria in the tumor microenvironment induce macrophage tolerance. Macrophage tolerance is a phenomenon of macrophage inability to respond to a repetitive inflammatory stimulus, which leads to a loss of cytotoxic activity. We studied the development of macrophage tolerance under the influence of bacteria and cytokines of the tumor microenvironment in vitro. It was found that the macrophage tolerance in the tumor stroma can develop in response to bacterial cell wall components and inflammatory factors. The acquired tolerance is inability of macrophages to produce proinflammatory cytokines TNFα, IL-1β, and MCP-1 and activation of the production of immunosuppressive IL-10.
Similar content being viewed by others
References
Kovaleva OV, Efremov GD, Mikhaylenko DS, Alekseev BY, Grachev AN. Role of tumor-associated macrophages in renal cell carcinoma pathogenesis. Onkourologiya. 2017;13(1):20-26. doi: https://doi.org/10.17650/1726-9776-2017-13-1-20-26
Biswas SK, Lopez-Collazo E. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends Immunol. 2009;30(10):475-487. doi: https://doi.org/10.1016/j.it.2009.07.009
Chen D, Xie J, Fiskesund R, Dong W, Liang X, Lv J, Jin X, Liu J, Mo S, Zhang T, Cheng F, Zhou Y, Zhang H, Tang K, Ma J, Liu Y, Huang B. Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. Nat. Commun. 2018;9(1):873. doi: https://doi.org/10.1038/s41467-018-03225-9
Ifrim DC, Quintin J, Joosten LA, Jacobs C, Jansen T, Jacobs L, Gow NA, Williams DL, van der Meer JW, Netea MG. Trained immunity or tolerance: opposing functional programs induced in human monocytes after engagement of various pattern recognition receptors. Clin. Vaccine Immunol. 2014;21(4):534-545. doi: https://doi.org/10.1128/CVI.00688-13
Kovaleva O, Podlesnaya P, Rashidova M, Samoilova D, Petrenko A, Zborovskaya I, Mochalnikova V, Kataev V, Khlopko Y, Plotnikov A, Gratchev A. Lung microbiome differentially impacts survival of patients with non-small cell lung cancer depending on tumor stroma phenotype. Biomedicines. 2020;8(9):349. doi: https://doi.org/10.3390/biomedicines8090349
Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677-686. doi: https://doi.org/10.1016/j.it.2004.09.015
Medvedev AE, Sabroe I, Hasday JD, Vogel SN. Tolerance to microbial TLR ligands: molecular mechanisms and relevance to disease. J. Endotoxin Res. 2006;12(3):133-150. doi: https://doi.org/10.1179/096805106X102255
Meng Y, Qu Y, Wu W, Chen L, Sun L, Tai G, Zhou Y, Cheng H. Galactan isolated from Cantharellus cibarius modulates antitumor immune response by converting tumor-associated macrophages toward M1-like phenotype. Carbohydr. Polym. 2019;226:115295. doi: https://doi.org/10.1016/j.carbpol.2019.115295
Nahid MA, Pauley KM, Satoh M, Chan EK. miR-146a is critical for endotoxin-induced tolerance: implication in innate immunity. J. Biol. Chem. 2009;284(50):34590-9. doi: https://doi.org/10.1074/jbc.M109.056317
Nejman D, Livyatan I, Fuks G, Gavert N, Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G, Gigi E, Meltser A, Douglas GM, Kamer I, Gopalakrishnan V, Dadosh T, Levin- Zaidman S, Avnet S, Atlan T, Cooper ZA, Arora R, Cogdill AP, Khan MAW, Ologun G, Bussi Y, Weinberger A, Lotan-Pompan M, Golani O, Perry G, Rokah M, Bahar-Shany K, Rozeman EA, Blank CU, Ronai A, Shaoul R, Amit A, Dorfman T, Kremer R, Cohen ZR, Harnof S, Siegal T, Yehuda-Shnaidman E, Gal-Yam EN, Shapira H, Baldini N, Langille MGI, Ben-Nun A, Kaufman B, Nissan A, Golan T, Dadiani M, Levanon K, Bar J, Yust-Katz S, Barshack I, Peeper DS, Raz DJ, Segal E, Wargo JA, Sandbank J, Shental N, Straussman R. The human tumor microbiome is composed of tumor typespecific intracellular bacteria. Science. 2020;368:973-980. doi: https://doi.org/10.1126/science.aay9189
Robert J. Comparative study of tumorigenesis and tumor immunity in invertebrates and nonmammalian vertebrates. Dev. Comp. Immunol. 2010;34(9):915-925. doi: https://doi.org/10.1016/j.dci.2010.05.011
Rodell CB, Arlauckas SP, Cuccarese MF, Garris CS, Li R, Ahmed MS, Kohler RH, Pittet MJ, Weissleder R. TLR7/8-agonist-loaded nanoparticles promote the polarization of tumourassociated macrophages to enhance cancer immunotherapy. Nat. Biomed. Eng. 2018;2(8):578-588. doi: https://doi.org/10.1038/s41551-018-0236-8
Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J. Clin. Invest. 2012;122(3):787-795. doi: https://doi.org/10.1172/JCI59643
Solinas G, Germano G, Mantovani A, Allavena P. Tumorassociated macrophages (TAM) as major players of the cancerrelated inflammation. J. Leukoc. Biol. 2009;86(5):1065-1073. doi: https://doi.org/10.1189/jlb.0609385
Widdrington JD, Gomez-Duran A, Pyle A, Ruchaud-Sparagano MH, Scott J, Baudouin SV, Rostron AJ, Lovat PE, Chinnery PF, Simpson AJ. Exposure of monocytic cells to lipopolysaccharide induces coordinated endotoxin tolerance, mitochondrial biogenesis, mitophagy, and antioxidant defenses. Front. Immunol. 2018;9:2217. doi: https://doi.org/10.3389/fimmu.2018.02217
Author information
Authors and Affiliations
Corresponding author
Additional information
Translated from Kletochnye Tekhnologii v Biologii i Meditsine, No. 4, pp. 250-254, December, 2021
Rights and permissions
About this article
Cite this article
Podlesnaya, P.A., Kovaleva, O.V., Petrenko, A.A. et al. The Mechanism of the Development of Macrophage Tolerance in Tumor Microenvironment. Bull Exp Biol Med 172, 653–657 (2022). https://doi.org/10.1007/s10517-022-05449-8
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10517-022-05449-8