靶向肿瘤相关巨噬细胞治疗卵巢癌的研究进展

doi:10.12280/gjfckx.20220189

摘要/Abstract

摘要：

卵巢癌是致死率最高的妇科恶性肿瘤，免疫因素在卵巢癌的发生、发展中起重要作用。肿瘤相关巨噬细胞（tumor-associated macrophages，TAMs）是卵巢癌肿瘤微环境中重要的免疫细胞，可分泌多种细胞因子促进癌细胞增殖及血管生成并抑制肿瘤免疫，在卵巢癌进展中发挥重要作用。因此，靶向TAMs治疗卵巢癌成为目前的研究热点之一。其具体治疗策略包括：抑制TAMs的募集、增强TAMs的吞噬能力、消耗TAMs、将M2型TAMs去极化为M1型TAMs或抑制TAMs向M2型极化以及阻断TAMs与肿瘤细胞的相互作用。目前，已有诸多基础研究证实化疗药物、免疫检查点阻断剂、纳米药物和中药调节TAMs治疗或协同治疗对卵巢癌具有一定疗效。综述靶向TAMs治疗卵巢癌的原理及相关进展，以期为其进一步研究及临床应用提供参考。

关键词: 卵巢肿瘤, 巨噬细胞, 表型, 分子靶向治疗, 免疫，细胞

Abstract:

Ovarian cancer (OC) remains the leading cause of death in gynecologic malignancies. Immune factors play an important role in its occurrence and development. Tumor-associated macrophages (TAMs) are important immune cells in the tumor microenvironment of OC, which can secrete a variety of cytokines to promote proliferation of cancers, angiogenesis and immunosuppression, playing an important role in the progress of OC. Therefore, targeted TAMs in the treatment of OC has become a research focus. The specific treatment strategies include blocking recruitment of TAMs, enhancing phagocytosis of TAMs, depleting TAMs, converting M2 TAMs to M1 TAMs or inhibiting M2 polarization of macrophages, blocking interactions between TAMs and OC. Numerous basic studies have confirmed that chemotherapeutic drugs, immune checkpoint blockers, nano-drugs and traditional Chinese medicines modulate TAMs to treat or synergistically treat OC to a certain extent. The principle and therapeutic progress of targeting TAMs in the treatment of OC will be reviewed, in order to provide reference for further researches and clinical applications.

Key words: Ovarian neoplasms, Macrophages, Phenotype, Molecular targeted therapy, Immunity, cellular

郑嘉慧, 林妍, 陈巧芬, 王雪峰. 靶向肿瘤相关巨噬细胞治疗卵巢癌的研究进展[J]. 国际妇产科学杂志, 2022, 49(6): 621-625.

ZHENG Jia-hui, LIN Yan, CHEN Qiao-fen, WANG Xue-feng. Research Progress of Targeting Tumor-Associated Macrophages Therapy for Ovarian Cancer[J]. Journal of International Obstetrics and Gynecology, 2022, 49(6): 621-625.

参考文献 33

[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[J]. CA Cancer J Clin, 2021, 71(3):209-249. doi: 10.3322/caac.21660. doi: 10.3322/caac.21660
[2]	Stewart C, Ralyea C, Lockwood S. Ovarian Cancer: An Integrated Review[J]. Semin Oncol Nurs, 2019, 35(2):151-156. doi: 10.1016/j.soncn.2019.02.001. doi: S0749-2081(19)30012-9 pmid: 30867104
[3]	屈丽媛, 龚时鹏. 肿瘤相关免疫细胞在卵巢癌中的作用及研究进展[J]. 妇产与遗传(电子版), 2020, 10(4):55-59. doi: 10.3868/j.issn.2095-1558.2020.04.012. doi: 10.3868/j.issn.2095-1558.2020.04.012
[4]	Kawamura K, Komohara Y, Takaishi K, et al. Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors[J]. Pathol Int, 2009, 59(5):300-305. doi: 10.1111/j.1440-1827.2009.02369.x. doi: 10.1111/j.1440-1827.2009.02369.x pmid: 19432671
[5]	Lan C, Huang X, Lin S, et al. Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer[J]. Technol Cancer Res Treat, 2013, 12(3):259-267. doi: 10.7785/tcrt.2012.500312. doi: 10.7785/tcrt.2012.500312
[6]	Moisan F, Francisco EB, Brozovic A, et al. Enhancement of paclitaxel and carboplatin therapies by CCL2 blockade in ovarian cancers[J]. Mol Oncol, 2014, 8(7):1231-1239. doi: 10.1016/j.molonc.2014.03.016. doi: 10.1016/j.molonc.2014.03.016 pmid: 24816187
[7]	Thaklaewphan P, Ruttanapattanakul J, Monkaew S, et al. Kaempferia parviflora extract inhibits TNF-α-induced release of MCP-1 in ovarian cancer cells through the suppression of NF-κB signaling[J]. Biomed Pharmacother, 2021, 141:111911. doi: 10.1016/j.biopha.2021.111911. doi: 10.1016/j.biopha.2021.111911 pmid: 34328090
[8]	Yang Q, Guo N, Zhou Y, et al. The role of tumor-associated macrophages (TAMs) in tumor progression and relevant advance in targeted therapy[J]. Acta Pharm Sin B, 2020, 10(11):2156-2170. doi: 10.1016/j.apsb.2020.04.004. doi: 10.1016/j.apsb.2020.04.004 pmid: 33304783
[9]	Jia XH, Du Y, Mao D, et al. Zoledronic acid prevents the tumor-promoting effects of mesenchymal stem cells via MCP-1 dependent recruitment of macrophages[J]. Oncotarget, 2015, 6(28):26018-26028. doi: 10.18632/oncotarget.4658. doi: 10.18632/oncotarget.4658
[10]	Murata Y, Kotani T, Ohnishi H, et al. The CD47-SIRPα signalling system: its physiological roles and therapeutic application[J]. J Biochem, 2014, 155(6):335-344. doi: 10.1093/jb/mvu017. doi: 10.1093/jb/mvu017 pmid: 24627525
[11]	Shimizu A, Sawada K, Kobayashi M, et al. Exosomal CD47 Plays an Essential Role in Immune Evasion in Ovarian Cancer[J]. Mol Cancer Res, 2021, 19(9):1583-1595. doi: 10.1158/1541-7786.MCR-20-0956. doi: 10.1158/1541-7786.MCR-20-0956 pmid: 34016744
[12]	Huang Y, Lv SQ, Liu PY, et al. A SIRPα-Fc fusion protein enhances the antitumor effect of oncolytic adenovirus against ovarian cancer[J]. Mol Oncol, 2020, 14(3):657-668. doi: 10.1002/1878-0261.12628. doi: 10.1002/1878-0261.12628 pmid: 31899582
[13]	Malfitano AM, Pisanti S, Napolitano F, et al. Tumor-Associated Macrophage Status in Cancer Treatment[J]. Cancers (Basel), 2020, 12(7):1987. doi: 10.3390/cancers12071987. doi: 10.3390/cancers12071987
[14]	Moughon DL, He H, Schokrpur S, et al. Macrophage Blockade Using CSF1R Inhibitors Reverses the Vascular Leakage Underlying Malignant Ascites in Late-Stage Epithelial Ovarian Cancer[J]. Cancer Res, 2015, 75(22):4742-4752. doi: 10.1158/0008-5472.CAN-14-3373. doi: 10.1158/0008-5472.CAN-14-3373 pmid: 26471360
[15]	Rodriguez-Garcia A, Lynn RC, Poussin M, et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy[J]. Nat Commun, 2021, 12(1):877. doi: 10.1038/s41467-021-20893-2. doi: 10.1038/s41467-021-20893-2 pmid: 33563975
[16]	Xia H, Li S, Li X, et al. Autophagic adaptation to oxidative stress alters peritoneal residential macrophage survival and ovarian cancer metastasis[J]. JCI Insight, 2020, 5(18):e141115. doi: 10.1172/jci.insight.141115. doi: 10.1172/jci.insight.141115
[17]	Prat M, Salon M, Allain T, et al. Murlentamab, a Low Fucosylated Anti-Müllerian Hormone Type II Receptor (AMHRII) Antibody, Exhibits Anti-Tumor Activity through Tumor-Associated Macrophage Reprogrammation and T Cell Activation[J]. Cancers (Basel), 2021, 13(8): 1845. doi: 10.3390/cancers13081845. doi: 10.3390/cancers13081845
[18]	Locatelli SL, Careddu G, Serio S, et al. Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530[J]. Clin Cancer Res, 2019, 25(3):1098-1112. doi: 10.1158/1078-0432.CCR-18-1133. doi: 10.1158/1078-0432.CCR-18-1133 pmid: 30352904
[19]	Feng Y, Xiao M, Zhang Z, et al. Potential interaction between lysophosphatidic acid and tumor-associated macrophages in ovarian carcinoma[J]. J Inflamm (Lond), 2020, 17:23. doi: 10.1186/s12950-020-00254-4. doi: 10.1186/s12950-020-00254-4
[20]	李乔, 尹如铁, 周乐, 等. IL-10免疫黏附素和肿瘤相关巨噬细胞对卵巢癌侵袭性的研究[J]. 华西药学杂志, 2017, 32(3):257-259. doi: 10.13375/j.cnki.wcjps.2017.03.011. doi: 10.13375/j.cnki.wcjps.2017.03.011
[21]	Zeng XY, Xie H, Yuan J, et al. M2-like tumor-associated macrophages-secreted EGF promotes epithelial ovarian cancer metastasis via activating EGFR-ERK signaling and suppressing lncRNA LIMT expression[J]. Cancer Biol Ther, 2019, 20(7):956-966. doi: 10.1080/15384047.2018.1564567. doi: 10.1080/15384047.2018.1564567
[22]	张海杏, 孟凡良, 龚时鹏. 肿瘤相关巨噬细胞在卵巢癌耐药中的作用[J]. 妇产与遗传(电子版), 2020, 10(3):51-55. doi: 10.3868/j.issn.2095-1558.2020.03.009. doi: 10.3868/j.issn.2095-1558.2020.03.009
[23]	Heath O, Berlato C, Maniati E, et al. Chemotherapy Induces Tumor-Associated Macrophages that Aid Adaptive Immune Responses in Ovarian Cancer[J]. Cancer Immunol Res, 2021, 9(6):665-681. doi: 10.1158/2326-6066.CIR-20-0968. doi: 10.1158/2326-6066.CIR-20-0968 pmid: 33839687
[24]	Natoli M, Herzig P, Pishali Bejestani E, et al. Plinabulin, a Distinct Microtubule-Targeting Chemotherapy, Promotes M1-Like Macrophage Polarization and Anti-tumor Immunity[J]. Front Oncol, 2021, 11:644608. doi: 10.3389/fonc.2021.644608. doi: 10.3389/fonc.2021.644608
[25]	Bonaventura P, Shekarian T, Alcazer V, et al. Cold Tumors: A Therapeutic Challenge for Immunotherapy[J]. Front Immunol, 2019, 10:168. doi: 10.3389/fimmu.2019.00168. doi: 10.3389/fimmu.2019.00168 pmid: 30800125
[26]	Gaillard SL, Secord AA, Monk B. The role of immune checkpoint inhibition in the treatment of ovarian cancer[J]. Gynecol Oncol Res Pract, 2016, 3:11. doi: 10.1186/s40661-016-0033-6. doi: 10.1186/s40661-016-0033-6
[27]	Wiehagen KR, Girgis NM, Yamada DH, et al. Combination of CD40 Agonism and CSF-1R Blockade Reconditions Tumor-Associated Macrophages and Drives Potent Antitumor Immunity[J]. Cancer Immunol Res, 2017, 5(12):1109-1121. doi: 10.1158/2326-6066.CIR-17-0258. doi: 10.1158/2326-6066.CIR-17-0258 pmid: 29097420
[28]	Kang Y, Flores L, Ngai HW, et al. Large, Anionic Liposomes Enable Targeted Intraperitoneal Delivery of a TLR 7/8 Agonist To Repolarize Ovarian Tumors′ Microenvironment[J]. Bioconjug Chem, 2021, 32(8):1581-1592. doi: 10.1021/acs.bioconjchem.1c00139. doi: 10.1021/acs.bioconjchem.1c00139
[29]	Haber T, Cornejo YR, Aramburo S, et al. Specific targeting of ovarian tumor-associated macrophages by large, anionic nanoparticles[J]. Proc Natl Acad Sci U S A, 2020, 117(33):19737-19745. doi: 10.1073/pnas.1917424117. doi: 10.1073/pnas.1917424117
[30]	Parayath NN, Gandham SK, Leslie F, et al. Improved anti-tumor efficacy of paclitaxel in combination with MicroRNA-125b-based tumor-associated macrophage repolarization in epithelial ovarian cancer[J]. Cancer Lett, 2019, 461:1-9. doi: 10.1016/j.canlet.2019.07.002. doi: S0304-3835(19)30390-8 pmid: 31288064
[31]	李溪. 姜黄素调控肿瘤相关巨噬细胞极化抑制卵巢癌恶性行为及其机制研究[D]. 上海: 海军军医大学, 2019.
[32]	Lee K, Ahn JH, Lee KT, et al. Deoxyschizandrin, Isolated from Schisandra Berries, Induces Cell Cycle Arrest in Ovarian Cancer Cells and Inhibits the Protumoural Activation of Tumour-Associated Macrophages[J]. Nutrients, 2018, 10(1):91. doi: 10.3390/nu10010091. doi: 10.3390/nu10010091
[33]	胡辉. 基于肿瘤相关巨噬细胞的极化探讨雷公藤内酯醇对耐顺铂上皮性卵巢癌抑制机制的研究[D]. 南昌: 南昌大学(医学院), 2020.