胆管癌肿瘤微环境与免疫治疗

陈顺; 王俊

doi:10.3969/j.issn.1001-5256.2022.10.044

胆管癌肿瘤微环境与免疫治疗

DOI: 10.3969/j.issn.1001-5256.2022.10.044

陈顺¹,
王俊^2, , ,

1.
广州中医药大学附属中山中医院(中山市中医院) 普外科，广东中山 528400
2.
湖南省人民医院肝胆外科，长沙 410005

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：陈顺负责资料分析，撰写论文；王俊负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
王俊，13973120355@139.com

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出版历程
- 收稿日期: 2022-03-08
- 录用日期: 2022-04-24
- 出版日期: 2022-10-20

Advances in tumor microenvironment and immunotherapy of Cholangiocarcinoma

Shun CHEN¹,
Jun WANG^{2
, ,
,}

1.
Depantment of General Surgery, Zhongshan Hospital of Traditional Chinese Medicine, Guangzhou University of Traditional Chinese Medicine, Zhongshan, Guangdong 528400, China
2.
Department of Hepatobiliary Surgery, Hunan Provincial People's Hospital, Changsha 410005, China

More Information

Corresponding author: Wang Jun, 13973120355@139.com(ORCID: 0000-0002-1596-8490)

摘要

摘要: 肿瘤微环境在胆管癌细胞增殖、促进肿瘤侵袭和转移过程中扮演重要角色，其复杂的作用机制，决定了胆管癌的异质性与恶性潜能，针对微环境中某些因子作为靶点进行抑制，重塑肿瘤微环境中免疫环境, 增强自然抗肿瘤免疫反应，经过改善的免疫环境和免疫功能在预测免疫治疗的反应性和确定新的治疗策略方面具有巨大的临床潜力，为胆管癌的定向治疗提供了潜在的研究方向。
- 胆管肿瘤 /
- 肿瘤微环境 /
- 免疫疗法
Abstract: The tumor microenvironment plays an important role in the proliferation, invasion and metastasis of cholangiocarcinoma cells. Complicated functional axis determines cholangiocarcinoma heterogeneity and its malignant potential. Targeting some factors in the tumor microenvironment might help reshape immune system of the tumor microenvironment to enhance natural anti-tumor immune responses. As a consequence, the improved immune environment and enhanced immune function will have great clinical potential in prediction of immune response to immunotherapy and identification of novel therapeutic strategies, which can provide a new potential direction for further investigation of targeted therapy of cholangiocarcinoma.
- Bile Duct Neoplasms /
- Tumor Microenvironment /
- Immunotherapy

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图 1 CCA微环境特点

Figure 1. CCA microenvironment characteristics

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参考文献(52)

[1]	SIRICA AE, GORES GJ, GROOPMAN JD, et al. Intrahepatic Cholangiocarcinoma: Continuing Challenges and Translational Advances[J]. Hepatology, 2019, 69(4): 1803-1815. DOI: 10.1002/hep.30289.
[2]	ESNAOLA NF, MEYER JE, KARACHRISTOS A, et al. Evaluation and management of intrahepatic and extrahepatic cholangiocarcinoma[J]. Cancer, 2016, 122(9): 1349-1369. DOI: 10.1002/cncr.29692.
[3]	LI W, WANG JH, JIANG XQ. Characteristics of immune microenvironment and progress of immune checkpoint inhibitors to cholangiocarcinoma treatment[J]. Chin J Hepatobiliary Surg, 2021, 27(6): 466-471. DOI: 10.3760/cma.j.cn113884-20200713-00369. 李炜, 王敬晗, 姜小清. 胆管癌免疫微环境特点与免疫检查点抑制剂治疗进展[J]. 中华肝胆外科杂志, 2021, 27(6): 466-471. DOI: 10.3760/cma.j.cn113884-20200713-00369.
[4]	VALLE JW, BORBATH I, KHAN SA, et al. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up[J]. Ann Oncol, 2016, 27(Suppl 5): v28-v37. DOI: 10.1093/annonc/mdw324.
[5]	HØGDALL D, O'ROURKE CJ, TARANTA A, et al. Molecular pathogenesis and current therapy in intrahepatic cholangiocarcinoma[J]. Dig Dis, 2016, 34(4): 440-451. DOI: 10.1159/000444562.
[6]	JIN MZ, JIN WL. The updated landscape of tumor microenvironment and drug repurposing[J]. Signal Transduct Target Ther, 2020, 5(1): 166. DOI: 10.1038/s41392-020-00280-x.
[7]	IOANNIDES CG, WHITESIDE TL. T cell recognition of human tumors: implications for molecular immunotherapy of cancer[J]. Clin Immunol Immunopathol, 1993, 66(2): 91-106. DOI: 10.1006/clin.1993.1012.
[8]	SIRICA AE, GORES GJ. Desmoplastic stroma and cholangiocarcinoma: clinical implications and therapeutic targeting[J]. Hepatology, 2014, 59(6): 2397-2402. DOI: 10.1002/hep.26762.
[9]	GENTILINI A, PASTORE M, MARRA F, et al. The role of stroma in cholangiocarcinoma: The intriguing interplay between fibroblastic component, immune cell subsets and tumor epithelium[J]. Int J Mol Sci, 2018, 19(10): 2885. DOI: 10.3390/ijms19102885.
[10]	SHA M, JEONG S, QIU BJ, et al. Isolation of cancer-associated fibroblasts and its promotion to the progression of intrahepatic cholangiocarcinoma[J]. Cancer Med, 2018, 7(9): 4665-4677. DOI: 10.1002/cam4.1704.
[11]	SIRICA AE. The role of cancer-associated myofibroblasts in intrahepatic cholangiocarcinoma[J]. Nat Rev Gastroenterol Hepatol, 2011, 9(1): 44-54. DOI: 10.1038/nrgastro.2011.222.
[12]	UTISPAN K, SONONGBUA J, THUWAJIT P, et al. Periostin activates integrin α5β1 through a PI3K/AKT-dependent pathway in invasion of cholangiocarcinoma[J]. Int J Oncol, 2012, 41(3): 1110-1118. DOI: 10.3892/ijo.2012.1530.
[13]	CHEN X, SONG E. Turning foes to friends: targeting cancer-associated fibroblasts[J]. Nat Rev Drug Discov, 2019, 18(2): 99-115. DOI: 10.1038/s41573-018-0004-1.
[14]	CHUAYSRI C, THUWAJIT P, PAUPAIROJ A, et al. Alpha-smooth muscle actin-positive fibroblasts promote biliary cell proliferation and correlate with poor survival in cholangiocarcinoma[J]. Oncol Rep, 2009, 21(4): 957-969. DOI: 10.3892/or_00000309.
[15]	KALLURI R. The biology and function of fibroblasts in cancer[J]. Nat Rev Cancer, 2016, 16(9): 582-598. DOI: 10.1038/nrc.2016.73.
[16]	FEIG C, JONES JO, KRAMAN M, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer[J]. Proc Natl Acad Sci U S A, 2013, 110(50): 20212-20217. DOI: 10.1073/pnas.1320318110.
[17]	YANG X, LIN Y, SHI Y, et al. FAP Promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3-CCL2 signaling[J]. Cancer Res, 2016, 76(14): 4124-4135. DOI: 10.1158/0008-5472.CAN-15-2973.
[18]	SIRET C, COLLIGNON A, SILVY F, et al. Deciphering the crosstalk between myeloid-derived suppressor cells and regulatory T cells in pancreatic ductal adenocarcinoma[J]. Front Immunol, 2019, 10: 3070. DOI: 10.3389/fimmu.2019.03070.
[19]	BEURY DW, PARKER KH, NYANDJO M, et al. Cross-talk among myeloid-derived suppressor cells, macrophages, and tumor cells impacts the inflammatory milieu of solid tumors[J]. J Leukoc Biol, 2014, 96(6): 1109-1118. DOI: 10.1189/jlb.3A0414-210R.
[20]	SEUBWAI W, KRAIKLANG R, WONGKHAM C, et al. Hypoxia enhances aggressiveness of cholangiocarcinoma cells[J]. Asian Pac J Cancer Prev, 2012, 13 Suppl: 53-58.
[21]	VANICHAPOL T, LEELAWAT K, HONGENG S. Hypoxia enhances cholangiocarcinoma invasion through activation of hepatocyte growth factor receptor and the extracellular signal-regulated kinase signaling pathway[J]. Mol Med Rep, 2015, 12(3): 3265-3272. DOI: 10.3892/mmr.2015.3865.
[22]	ROBERT C. A decade of immune-checkpoint inhibitors in cancer therapy[J]. Nat Commun, 2020, 11(1): 3801. DOI: 10.1038/s41467-020-17670-y.
[23]	KOURY J, LUCERO M, CATO C, et al. Immunotherapies: Exploiting the immune system for cancer treatment[J]. J Immunol Res, 2018, 2018: 9585614. DOI: 10.1155/2018/9585614.
[24]	MERTENS JC, FINGAS CD, CHRISTENSEN JD, et al. Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma[J]. Cancer Res, 2013, 73(2): 897-907. DOI: 10.1158/0008-5472.CAN-12-2130.
[25]	MAHIPAL A, TELLA SH, KOMMALAPATI A, et al. FGFR2 genomic aberrations: Achilles heel in the management of advanced cholangiocarcinoma[J]. Cancer Treat Rev, 2019, 78: 1-7. DOI: 10.1016/j.ctrv.2019.06.003.
[26]	NAKAMURA H, ARAI Y, TOTOKI Y, et al. Genomic spectra of biliary tract cancer[J]. Nat Genet, 2015, 47(9): 1003-1010. DOI: 10.1038/ng.3375.
[27]	JAVLE M, LOWERY M, SHROFF RT, et al. Phase Ⅱ study of BGJ398 in patients with FGFR-altered advanced cholangiocarcinoma[J]. J Clin Oncol, 2018, 36(3): 276-282. DOI: 10.1200/JCO.2017.75.5009.
[28]	MAZZAFERRO V, EL-RAYES BF, DROZ DIT BUSSET M, et al. Derazantinib (ARQ 087) in advanced or inoperable FGFR2 gene fusion-positive intrahepatic cholangiocarcinoma[J]. Br J Cancer, 2019, 120(2): 165-171. DOI: 10.1038/s41416-018-0334-0.
[29]	LING H, ROUX E, HEMPEL D, et al. Transforming growth factor β neutralization ameliorates pre-existing hepatic fibrosis and reduces cholangiocarcinoma in thioacetamide-treated rats[J]. PLoS One, 2013, 8(1): e54499. DOI: 10.1371/journal.pone.0054499.
[30]	THONGCHOT S, FERRARESI A, VIDONI C, et al. Resveratrol interrupts the pro-invasive communication between cancer associated fibroblasts and cholangiocarcinoma cells[J]. Cancer Lett, 2018, 430: 160-171. DOI: 10.1016/j.canlet.2018.05.031.
[31]	ZUO S, CHEN Q, ZOU WL. Current status and prospect of immunotherapy for cholangiocarcinoma[J]. Chin J Dig Surg, 2022, 21(7): 873-879. DOI: 10.3760/cma.j.cn115610-20220506-00254. 左石, 陈乾, 邹卫龙. 胆管癌免疫治疗的现状与展望[J]. 中华消化外科杂志, 2022, 21(7): 873-879. DOI: 10.3760/cma.j.cn115610-20220506-00254.
[32]	MASSARWEH NN, EL-SERAG HB. Epidemiology of hepatocellular carcinoma and intrahepatic cholangiocarcinoma[J]. Cancer Control, 2017, 24(3): 1073274817729245. DOI: 10.1177/1073274817729245.
[33]	JUSAKUL A, CUTCUTACHE I, YONG CH, et al. Whole-genome and epigenomic landscapes of etiologically distinct subtypes of cholangiocarcinoma[J]. Cancer Discov, 2017, 7(10): 1116-1135. DOI: 10.1158/2159-8290.CD-17-0368.
[34]	FARSHIDFAR F, ZHENG S, GINGRAS MC, et al. Integrative genomic analysis of cholangiocarcinoma identifies distinct IDH-mutant molecular profiles[J]. Cell Rep, 2017, 19(13): 2878-2880. DOI: 10.1016/j.celrep.2017.06.008.
[35]	GUO D, REINITZ F, YOUSSEF M, et al. An LXR agonist promotes glioblastoma cell death through inhibition of an EGFR/AKT/SREBP-1/LDLR-dependent pathway[J]. Cancer Discov, 2011, 1(5): 442-456. DOI: 10.1158/2159-8290.CD-11-0102.
[36]	TAVAZOIE MF, POLLACK I, TANQUECO R, et al. LXR/ApoE activation restricts innate immune suppression in cancer[J]. Cell, 2018, 172(4): 825-840. e18. DOI: 10.1016/j.cell.2017.12.026.
[37]	LOEUILLARD E, YANG J, BUCKARMA E, et al. Targeting tumor-associated macrophages and granulocytic myeloid-derived suppressor cells augments PD-1 blockade in cholangiocarcinoma[J]. J Clin Invest, 2020, 130(10): 5380-5396. DOI: 10.1172/JCI137110.
[38]	JUNKING M, GRAINOK J, THEPMALEE C, et al. Enhanced cytotoxic activity of effector T-cells against cholangiocarcinoma by dendritic cells pulsed with pooled mRNA[J]. Tumour Biol, 2017, 39(10): 1010428317733367. DOI: 10.1177/1010428317733367.
[39]	CHANG J, GU YC, LI XC. Research advances of immune checkpoint inhibitors in the treatment of cholangiocarcinoma[J]. Chin J Dig Surg, 2021, 20(2): 250-254. DOI: 10.3760/cma.j.cn115610-20210122-00037. 长江, 顾轶超, 李相成. 胆管癌免疫检查点抑制剂治疗研究进展[J]. 中华消化外科杂志, 2021, 20(2): 250-254. DOI: 10.3760/cma.j.cn115610-20210122-00037.
[40]	PARDOLL DM. The blockade of immune checkpoints in cancer immunotherapy[J]. Nat Rev Cancer, 2012, 12(4): 252-264. DOI: 10.1038/nrc3239.
[41]	ZHU Y, WANG XY, ZHANG Y, et al. Programmed death ligand 1 expression in human intrahepatic cholangiocarcinoma and its association with prognosis and CD8⁺ T-cell immune responses[J]. Cancer Manag Res, 2018, 10: 4113-4123. DOI: 10.2147/CMAR.S172719.
[42]	LU JC, ZENG HY, SUN QM, et al. Distinct PD-L1/PD1 profiles and clinical implications in intrahepatic cholangiocarcinoma patients with different risk factors[J]. Theranostics, 2019, 9(16): 4678-4687. DOI: 10.7150/thno.36276.
[43]	YE Y, ZHOU L, XIE X, et al. Interaction of B7-H1 on intrahepatic cholangiocarcinoma cells with PD-1 on tumor-infiltrating T cells as a mechanism of immune evasion[J]. J Surg Oncol, 2009, 100(6): 500-504. DOI: 10.1002/jso.21376.
[44]	LE DT, DURHAM JN, SMITH KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade[J]. Science, 2017, 357(6349): 409-413. DOI: 10.1126/science.aan6733.
[45]	ASAOKA Y, IJICHI H, KOIKE K. PD-1 blockade in tumors with mismatch-repair deficiency[J]. N Engl J Med, 2015, 373(20): 1979. DOI: 10.1056/NEJMc1510353.
[46]	KANG J, JEONG JH, HWANG HS, et al. Efficacy and safety of pembrolizumab in patients with refractory advanced biliary tract cancer: Tumor proportion score as a potential biomarker for response[J]. Cancer Res Treat, 2020, 52(2): 594-603. DOI: 10.4143/crt.2019.493.
[47]	KIM RD, CHUNG V, ALESE OB, et al. A Phase 2 multi-institutional study of nivolumab for patients with advanced refractory biliary tract cancer[J]. JAMA Oncol, 2020, 6(6): 888-894. DOI: 10.1001/jamaoncol.2020.0930.
[48]	IOKA T, UENO M, OH DY, et al. Evaluation of safety and tolerability of durvalumab (D) with or without tremelimumab (T) in patients (pts) with biliary tract cancer (BTC)[J]. J Clin Oncol, 2019, 37(4_suppl): 387. DOI: 10.1200/JCO.2019.37.4_suppl.387
[49]	ZHOU G, SPRENGERS D, MANCHAM S, et al. Reduction of immunosuppressive tumor microenvironment in cholangiocarcinoma by ex vivo targeting immune checkpoint molecules[J]. J Hepatol, 2019, 71(4): 753-762. DOI: 10.1016/j.jhep.2019.05.026.
[50]	ABOU-ALFA GK, SAHAI V, HOLLEBECQUE A, et al. Pemigatinib for previously treated, locally advanced or metastatic cholangiocarcinoma: a multicentre, open-label, phase 2 study[J]. Lancet Oncol, 2020, 21(5): 671-684. DOI: 10.1016/S1470-2045(20)30109-1.
[51]	ARKENAU HT, MARTIN-LIBERAL J, CALVO E, et al. Ramucirumab plus pembrolizumab in patients with previously treated advanced or metastatic biliary tract cancer: Nonrandomized, Open-Label, Phase I Trial (JVDF)[J]. Oncologist, 2018, 23(12): 1407-1407, e136. DOI: 10.1634/theoncologist.2018-0044.
[52]	SMITH HJ, MCCAW TR, LONDONO AI, et al. The antitumor effects of entinostat in ovarian cancer require adaptive immunity[J]. Cancer, 2018, 124(24): 4657-4666. DOI: 10.1002/cncr.31761.