Immunohistochemical diagnosis of tumor-associated macrophages in patients with muscle-invasive bladder cancer after radical cystectomy

Abstract

BACKGROUND: Bladder cancer is a serious problem of oncourology. The gold standard of treatment for muscle-invasive bladder cancer is radical cystectomy with previous neoadjuvant chemotherapy. Unfortunately, the effectiveness of radical treatments is severely limited in the long term. For this reason, research in the field of predicting survival can significantly improve long-term oncological results. The determination of the levels of macrophages associated with the tumor appears promising.

AIM: to determine the effect of the expression levels of macrophages associated with a tumor on survival rates in patients diagnosed with muscle-invasive bladder cancer after radical cystectomy.

MATERIALS AND METHODS: the study was conducted on the basis of the Clinic of the Bashkir State Medical University in the period from 01.05.2021 to 01.07.2023. The study involved 66 patients with an established diagnosis of muscle-invasive bladder cancer. After surgical treatment, histological and immunohistochemical studies were performed to determine CD68 and CD163 levels. After 24 months, a survival analysis was performed to determine the levels of general, tumor-specific and relapse-free survival and the construction of Kaplan–Mayer graphs.

RESULTS: According to the results of the analysis, there was a significant decrease in survival in groups with high CD68 and CD163 expression rates (p < 0.05). In the study groups, there was a significantly significant correlation between high levels of CD68 and CD163 (p < 0.05).

CONCLUSIONS: CD68 and CD163 can act as independent markers of predicted survival in patients with muscle-invasive bladder cancer after radical cystectomy.

Keywords

bladder cancer / radical cystectomy / macrophages / immunohistochemical diagnostics / CD68 / CD163

References

[1] Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021:71(3):209–249. DOI: 10.3322/caac.21660

[2] Sung H., Ferlay J., Siegel R.L., et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries // CA Cancer J Clin. 2021. Vol. 71, No. 3. P. 209–249. DOI: 10.3322/caac.21660

[3] Koll FJ, Banek S, Kluth L, et al. Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis. J Transl Med. 2023;21(1):124. DOI: 10.1186/s12967-023-03949-3

[4] Koll F.J., Banek S., Kluth L., et al. Tumor-associated macrophages and Tregs influence and represent immune cell infiltration of muscle-invasive bladder cancer and predict prognosis // J Transl Med. 2023. Vol. 21, No. 1. P. 124. DOI: 10.1186/s12967-023-03949-3

[5] Schneider AK, Chevalier MF, Derré L. The multifaceted immune regulation of bladder cancer. Nat Rev Urol. 2019;16(10):613–630. DOI: 10.1038/s41585-019-0226-y

[6] Schneider A.K., Chevalier M.F., Derré L. The multifaceted immune regulation of bladder cancer // Nat Rev Urol. 2019. Vol. 16, No. 10. P. 613–630. DOI: 10.1038/s41585-019-0226-y

[7] Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines. Eur Urol. 2021;79(1):82–104. DOI: 10.1016/j.eururo.2020.03.055

[8] Witjes J.A., Bruins H.M., Cathomas R., et al. European Association of Urology Guidelines on Muscle-invasive and Metastatic Bladder Cancer: Summary of the 2020 Guidelines // Eur Urol. 2021. Vol. 79, No. 1. P. 82–104. DOI: 10.1016/j.eururo.2020.03.055

[9] Zehnder P, Studer UE, Skinner EC, et al. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades. BJU Int. 2013;112(2):E51–E58. DOI: 10.1111/bju.12215

[10] Zehnder P., Studer U.E., Skinner E.C., et al. Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades // BJU Int. 2013. Vol. 112, No. 2. P. E51–E58. DOI: 10.1111/bju.12215

[11] Wang M, Zhao J, Zhang L, et al. Role of tumor microenvironment in tumorigenesis. J Cancer. 2017;8(5):761–773. DOI: 10.7150/jca.17648

[12] Wang M., Zhao J., Zhang L., et al. Role of tumor microenvironment in tumorigenesis // J Cancer. 2017. Vol. 8, No. 5. P. 761–773. DOI: 10.7150/jca.17648

[13] Ocaña MC, Martínez-Poveda B, Quesada AR, et al. Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target. Med Res Rev. 2019;39(1):70–113. DOI: 10.1002/med.21511

[14] Ocaña M.C., Martínez-Poveda B., Quesada A.R., et al. Metabolism within the tumor microenvironment and its implication on cancer progression: an ongoing therapeutic target // Med Res Rev 2019. Vol. 39, No. 1. P. 70–113. DOI: 10.1002/med.21511

[15] Hatogai K, Sweis RF. The tumor microenvironment of bladder cancer. Adv Exp Med Biol. 2020;1296:275–290. DOI: 10.1007/9783-030-59038-3_17

[16] Hatogai K., Sweis R.F. The tumor microenvironment of bladder cancer // Adv Exp Med Biol. 2020. Vol. 1296. P. 275–290. DOI: 10.1007/9783-030-59038-3_17

[17] Najafi M, Hashemi Goradel N, Farhood B, et al. Macrophage polarity in cancer: A review. J Cell Biochem. 2019;120(3):2756–2765. DOI: 10.1002/jcb.27646

[18] Najafi M., Hashemi Goradel N., Farhood B., et al. Macrophage polarity in cancer: A review // J Cell Biochem. 2019. Vol. 120, No. 3. P. 2756–2765. DOI: 10.1002/jcb.27646

[19] Li X, Liu R, Su X, et al. Harnessing tumor-associated macrophages as aids for cancer immunotherapy. Mol Cancer. 2019;18(1):177. DOI: 10.1186/s12943-019-1102-3

[20] Li X., Liu R., Su X., et al. Harnessing tumor-associated macrophages as aids for cancer immunotherapy // Mol Cancer. 2019. Vol. 18, No. 1. P. 177. DOI: 10.1186/s12943-019-1102-3

[21] Cioni B, Zaalberg A, van Beijnum JR, et al. Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion. Nat Commun. 2020;11(1):4498. DOI: 10.1038/s41467-020-18313-y

[22] Cioni B., Zaalberg A., van Beijnum J.R., et al. Androgen receptor signalling in macrophages promotes TREM-1-mediated prostate cancer cell line migration and invasion // Nat Commun. 2020. Vol. 11, No. 1. P. 4498. DOI: 10.1038/s41467-020-18313-y

[23] Chanmee T, Ontong P, Konno K, et al. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6(3):1670–1690. DOI: 10.3390/cancers6031670

[24] Chanmee T., Ontong P., Konno K., et al. Tumor-associated macrophages as major players in the tumor microenvironment // Cancers (Basel). 2014. Vol. 6, No. 3. P. 1670–1690. DOI: 10.3390/cancers6031670

[25] Mantovani A, Sozzani S, Locati M, et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549–555. DOI: 10.1016/s1471-4906(02)02302-5

[26] Mantovani A., Sozzani S., Locati M., et al. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes // Trends Immunol. 2002. Vol. 23, No. 11. P. 549–555. DOI: 10.1016/s1471-4906(02)02302-5

[27] Martínez VG, Rubio C, Martínez-Fernández M, et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer. Clin Cancer Res. 2017;23(23):7388–7399. DOI: 10.1158/1078-0432.CCR-17-1004

[28] Martínez V.G., Rubio C., Martínez-Fernández M., et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder cancer // Clin Cancer Res. 2017. Vol. 23, No. 23. P. 7388–7399. DOI: 10.1158/1078-0432.CCR-17-1004

[29] Prima V, Kaliberova LN, Kaliberov S, et al. COX2/mPGES1/ PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells. Proc Natl Acad Sci USA. 2017;114(5):1117–1122. DOI: 10.1073/pnas.1612920114

[30] Prima V., Kaliberova L.N., Kaliberov S., et al. COX2/mPGES1/ PGE2 pathway regulates PD-L1 expression in tumor-associated macrophages and myeloid-derived suppressor cells // Proc Natl Acad Sci USA. 2017. Vol. 114, No. 5. P. 1117–1122. DOI: 10.1073/pnas.1612920114

[31] Wu ATH, Srivastava P, Yadav VK, et al. Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/β-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages. Toxicol Appl Pharmacol. 2020;401:115109. DOI: 10.1016/j.taap.2020.115109

[32] Wu A.T.H., Srivastava P., Yadav V.K., et al. Ovatodiolide, isolated from Anisomeles indica, suppresses bladder carcinogenesis through suppression of mTOR/β-catenin/CDK6 and exosomal miR-21 derived from M2 tumor-associated macrophages // Toxicol Appl Pharmacol. 2020. Vol. 401. P. 115109. DOI: 10.1016/j.taap.2020.115109

[33] Wang X, Ni S, Chen Q, et al. Bladder cancer cells induce immunosuppression of T cells by supporting PD-L1 expression in tumour macrophages partially through interleukin 10. Cell Biol Int. 2017;41(2):177–186. DOI: 10.1002/cbin.10716

[34] Wang X., Ni S., Chen Q., et al. Bladder cancer cells induce immunosuppression of T cells by supporting PD-L1 expression in tumour macrophages partially through interleukin 10 // Cell Biol Int 2017. Vol. 41, No. 2. P. 177–186. DOI: 10.1002/cbin.10716

[35] Zhao Y, Wang D, Xu T, et al. Bladder cancer cells re-educate TAMs through lactate shuttling in the microfluidic cancer microenvironment. Oncotarget. 2015;6(36):39196–39210. DOI: 10.18632/oncotarget.5538

[36] Zhao Y., Wang D., Xu T., et al. Bladder cancer cells re-educate TAMs through lactate shuttling in the microfluidic cancer microenvironment // Oncotarget 2015. Vol. 6, No. 36. P. 39196–39210. DOI: 10.18632/oncotarget.5538

[37] Leblond MM, Zdimerova H, Desponds E, et al. Tumor-associated macrophages in bladder cancer: biological role, impact on therapeutic response and perspectives for immunotherapy. Cancers (Basel). 2021;13(18):4712. DOI: 10.3390/cancers13184712

[38] Leblond M.M., Zdimerova H., Desponds E., et al. Tumor-associated macrophages in bladder cancer: biological role, impact on therapeutic response and perspectives for immunotherapy // Cancers (Basel). 2021. Vol. 13, No. 18. P. 4712. DOI: 10.3390/cancers13184712

[39] Xue Y, Tong L, LiuAnwei Liu F, et al. Tumor-infiltrating M2 macrophages driven by specific genomic alterations are associated with prognosis in bladder cancer. Oncol Rep. 2019;42(2):581–594. DOI: 10.3892/or.2019.7196

[40] Xue Y., Tong L., LiuAnwei Liu F., et al. Tumor-infiltrating M2 macrophages driven by specific genomic alterations are associated with prognosis in bladder cancer // Oncol Rep. 2019. Vol. 42, No. 2. P. 581–594. DOI: 10.3892/or.2019.7196

[41] Lobo N, Mount C, Omar K, et al. Landmarks in the treatment of muscle-invasive bladder cancer. Nat Rev Urol. 2017;14(9):565–574. DOI: 10.1038/nrurol.2017.82

[42] Lobo N., Mount C., Omar K., et al. Landmarks in the treatment of muscle-invasive bladder cancer // Nat Rev Urol. 2017. Vol. 14, No. 9. P. 565–574. DOI: 10.1038/nrurol.2017.82

[43] Zeng H, Liu Z, Wang Z, et al. Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses. Int J Cancer. 2020;146(2):542–552. DOI: 10.1002/ijc.32715

[44] Zeng H., Liu Z., Wang Z., et al. Intratumoral IL22-producing cells define immunoevasive subtype muscle-invasive bladder cancer with poor prognosis and superior nivolumab responses // Int J Cancer. 2020. Vol. 146, No. 2. P. 542–552. DOI: 10.1002/ijc.32715

[45] Sun M, Zeng H, Jin K, et al. Infiltration and polarization of tumor-associated macrophages predict prognosis and therapeutic benefit in muscle-invasive bladder cancer. Cancer Immunol Immunother. 2022;71(6):1497–1506. DOI: 10.1007/s00262-021-03098-w

[46] Sun M., Zeng H., Jin K., et al. Infiltration and polarization of tumor-associated macrophages predict prognosis and therapeutic benefit in muscle-invasive bladder cancer // Cancer Immunol Immunother. 2022. Vol. 71, No. 6. P. 1497–1506. DOI: 10.1007/s00262-021-03098-w

[47] Taubert H, Eckstein M, Epple E, et al. Immune cell-associated protein expression helps to predict survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and optional adjuvant chemotherapy. Cells. 2021;10(1):159. DOI: 10.3390/cells10010159

[48] Taubert H., Eckstein M., Epple E., et al. Immune cell-associated protein expression helps to predict survival in muscle-invasive urothelial bladder cancer patients after radical cystectomy and optional adjuvant chemotherapy // Cells. 2021. Vol. 10, No. 1. P. 159. DOI: 10.3390/cells10010159

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