肝细胞癌免疫微环境与免疫抑制治疗的研究进展

摘要/Abstract

摘要： 肝细胞癌(HCC)被认为是一种免疫原性肿瘤,在慢性肝炎和肝硬化的人群中发病率更高。尽管近年来分子靶向药物等系统性治疗取得了巨大进展,但由于耐药和频繁的复发和转移,HCC仍是预后最差的几种癌症之一。近年来,癌症免疫抑制治疗等新的治疗策略延长了患者的生命。然而,一种单独的免疫疗法对癌症,特别是实体肿瘤的治疗效果有限。因此,需要有效的免疫治疗组合,如检查点抑制剂(ICIs)和免疫抑制细胞治疗的组合。本文将讨论当前免疫抑制细胞的概念,包括肿瘤相关巨噬细胞(TAMs)、骨髓源性抑制细胞(MDSCs)、肿瘤相关中性粒细胞(TANs)、癌症相关成纤维细胞(CAFs)和调节性T细胞(Tregs),以及免疫抑制治疗的现状,并对未来的发展前景进行展望。

关键词: 肝细胞癌, 肿瘤微环境, 免疫抑制治疗, 联合治疗

冉君, 屈献乐, 肖彬彬, 马红梅. 肝细胞癌免疫微环境与免疫抑制治疗的研究进展[J]. 肝脏, 2022, 27(7): 825-828.

参考文献

[1] Dong P, Ma L, Liu L, et al. CD86(+)/CD206(+), Diametrically Polarized Tumor-Associated Macrophages, Predict Hepatocellular Carcinoma Patient Prognosis. Int J Mol Sci,2016,17:320.
[2] Zhu Y, Yang J, Xu D, et al. Disruption of tumour-associated macrophage trafficking by the osteopontin-induced colony-stimulating factor-1 signalling sensitises hepatocellular carcinoma to anti-PD-L1 blockade. Gut,2019,68:1653-1666.
[3] Li X, Yao W, Yuan Y, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut,2017,66:157-167.
[4] Wu L, Zhang X, Zheng L, et al. RIPK3 Orchestrates Fatty Acid Metabolism in Tumor-Associated Macrophages and Hepatocarcinogenesis. Cancer Immunol Res,2020,8:710-721.
[5] Chi X, Yan R, Zhang J, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science,2020,369:650-655.
[6] Yang Y, Ye YC, Chen Y, et al. Crosstalk between hepatic tumor cells and macrophages via Wnt/beta-catenin signaling promotes M2-like macrophage polarization and reinforces tumor malignant behaviors. Cell Death Dis,2018,9:793.
[7] Zhou J, Ding T, Pan W, et al. Increased intratumoral regulatory T cells are related to intratumoral macrophages and poor prognosis in hepatocellular carcinoma patients. Int J Cancer, 2009,125:1640-1648.
[8] Zhou J, Liu M, Sun H, et al. Hepatoma-intrinsic CCRK inhibition diminishes myeloid-derived suppressor cell immunosuppression and enhances immune-checkpoint blockade efficacy. Gut, 2018,67:931-944.
[9] Chiu DK, Tse AP, Xu IM, et al. Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nat Commun,2017,8:517.
[10] Wang W, Wu J, Ji M, et al. Exogenous interleukin-33 promotes hepatocellular carcinoma growth by remodelling the tumour microenvironment. J Transl Med,2020,18:477.
[11] Wang N, Tan HY, Lu Y, et al. PIWIL1 governs the crosstalk of cancer cell metabolism and immunosuppressive microenvironment in hepatocellular carcinoma. Signal Transduct Target Ther,2021,6:86.
[12] Limagne E, Richard C, Thibaudin M, et al. Tim-3/galectin-9 pathway and mMDSC control primary and secondary resistances to PD-1 blockade in lung cancer patients. Oncoimmunology, 2019,8:e1564505.
[13] Zhou SL, Zhou ZJ, Hu ZQ, et al. Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology,2016,150:1646-1658 e17.
[14] Xu X, Ye L, Zhang Q, et al. Group-2 Innate Lymphoid Cells Promote Hepatocellular Carcinoma Progression via CXCL2-Neutrophil Induced Immunosuppression. Hepatology,2021.
[15] Zhou SL, Yin D, Hu ZQ, et al. A Positive Feedback Loop Between Cancer Stem-Like Cells and Tumor-Associated Neutrophils Controls Hepatocellular Carcinoma Progression. Hepatology, 2019,70:1214-1230.
[16] Mano Y, Yoshio S, Shoji H, et al. Bone morphogenetic protein 4 provides cancer-supportive phenotypes to liver fibroblasts in patients with hepatocellular carcinoma. J Gastroenterol, 2019,54:1007-1018.
[17] Li T, Yang Y, Hua X, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett,2012,318:154-161.
[18] Cheng JT, Deng YN, Yi HM, et al. Hepatic carcinoma-associated fibroblasts induce IDO-producing regulatory dendritic cells through IL-6-mediated STAT3 activation. Oncogenesis, 2016,5:e198.
[19] Yang XH, Yamagiwa S, Ichida T, et al. Increase of CD4⁺ CD25⁺ regulatory T-cells in the liver of patients with hepatocellular carcinoma. J Hepatol,2006,45:254-262.
[20] Cao M, Cabrera R, Xu Y, et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+)CD25(+) regulatory T cells. Lab Invest,2007,87:582-590.
[21] Jiang R, Tang J, Chen Y, et al. The long noncoding RNA lnc-EGFR stimulates T-regulatory cells differentiation thus promoting hepatocellular carcinoma immune evasion. Nat Commun, 2017,8:15129.
[22] Chang CP, Su YC, Lee PH, et al. Targeting NFKB by autophagy to polarize hepatoma-associated macrophage differentiation. Autophagy,2013,9:619-621.
[23] Yao W, Ba Q, Li X, et al. A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine, 2017,22:58-67.
[24] Hansen J, Baum A, Pascal KE, et al. Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail. Science,2020,369:1010-1014.
[25] Liu D, Li G, Avella DM, et al. Sunitinib represses regulatory T cells to overcome immunotolerance in a murine model of hepatocellular cancer. Oncoimmunology, 2017,7:e1372079.
[26] Cheng C, Shou Q, Lang J, et al. Gehua Jiecheng Decoction Inhibits Diethylnitrosamine-Induced Hepatocellular Carcinoma in Mice by Improving Tumor Immunosuppression Microenvironment. Front Pharmacol,2020,11:809.
[27] Wang Q, Yu T, Yuan Y, et al. Sorafenib reduces hepatic infiltrated regulatory T cells in hepatocellular carcinoma patients by suppressing TGF-beta signal. J Surg Oncol,2013,107:422-447.
[28] Sangro B, Gomez-Martin C, de la Mata M, et al. A clinical trial of CTLA-4 blockade with tremelimumab in patients with hepatocellular carcinoma and chronic hepatitis C. J Hepatol, 2013,59:81-88.
[29] El-Khoueiry AB, Sangro B, Yau T, et al. Nivolumab in patients with advanced hepatocellular carcinoma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet,2017,389:2492-2502.
[30] Yau T, Park JW, Finn RS, et al. CheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Ann Oncol,2019,30:v874-v875.
[31] Lee CH, Lee YB, Kim MA, et al. Effectiveness of nivolumab versus regorafenib in hepatocellular carcinoma patients who failed sorafenib treatment. Clin Mol Hepatol, 2020,26:328-339.
[32] Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol,2018,19:940-952.
[33] Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med 2020;382:1894-1905.
[34] Kudo M. Immuno-Oncology Therapy for Hepatocellular Carcinoma: Current Status and Ongoing Trials. Liver Cancer,2019,8:221-238.
[35] Yau T, Kang YK, Kim TY, et al. Efficacy and Safety of Nivolumab Plus Ipilimumab in Patients With Advanced Hepatocellular Carcinoma Previously Treated With Sorafenib: The CheckMate 040 Randomized Clinical Trial. JAMA Oncol,2020,6:e204564.