肠道菌群和瘤内菌群失调在肝细胞癌免疫逃逸中的研究进展  

Progress of intestinal flora and intratumoral flora imbalance in immune escape of hepatocellular carcinoma

作　　者：相乐阳 古建仪 周俊臻 沈威鹏 张清[3] 曹明溶[1] 蒋建伟[2] XIANG Leyang;GU Jianyi;ZHOU Junzhen;SHEN Weipeng;ZHANG Qing;CAO Mingrong;JIANG Jianwei(Department of Hepatobiliary Surgery,the First Affiliated Hospital,Jinan University,Guangzhou 510630,Guangdong,China;Department of Biochemistry and Molecular Biology,School of Basic Medicine and Public Health,Jinan University,Guangzhou 510632,Guangdong,China;Department of Breast Surgery,the First Affiliated Hospital,Jinan University,Guangzhou 510630,Guangdong,China)

机构地区：[1]暨南大学附属第一医院肝胆外科,广东广州510630 [2]暨南大学基础医学与公共卫生学院生物化学与分子生物学系,广东广州510632 [3]暨南大学附属第一医院乳腺外科,广东广州510630

出　　处：《暨南大学学报（自然科学与医学版）》2024年第2期111-123,共13页Journal of Jinan University(Natural Science & Medicine Edition)

基　　金：广东省医学科学技术研究基金项目(A2023141);广东省自然科学基金项目(2114050002009);暨南大学附属第一医院普通外科旗舰学科建设科研经费项目(711003);吴阶平医学基金会临床科研专项资助基金项目(320.6750.2020-20-5)。

摘　　要：近年来,免疫治疗在不可切除肝细胞癌(HCC)的系统治疗中发挥了重要的作用并逐渐跻身一线治疗方案。即使目前各个指南均推荐一线使用的阿替利珠单抗联合贝伐珠单抗方案,其对HCC患者的客观缓解率等指标仍有较大的提升空间,部分原因在于大量HCC患者对免疫治疗有原发性耐药,导致肿瘤免疫逃逸。肿瘤免疫逃逸与肿瘤微环境因素和肿瘤内因素密切相关。研究发现HCC患者广泛存在菌群失调,包括肠道菌群失调及瘤内菌群丰度的改变,前者可能通过脂多糖、菌群代谢产物(如次级胆汁酸和短链脂肪酸)或自身的结构蛋白等与肿瘤微环境中的免疫细胞相互作用,后者可能在HCC细胞或免疫细胞内直接参与基因表观遗传学水平表达和物质代谢的调控,进而改变HCC细胞的生物学特性和肿瘤微环境,诱导抑制性肿瘤微环境,引起HCC细胞免疫逃逸。本文对HCC患者中菌群失调的类型进行了归纳总结,并从肠道菌群和瘤内菌群两方面对HCC免疫逃逸的可能机制进行综述,以期为探究HCC患者菌群与免疫治疗耐药之间的关系提供参考。In recent years,immunotherapy plays an important role in the systematic treatment of unresectable hepatocellular carcinoma(HCC)and gradually becomes one of the first-line treatments.However,the objective remission rate of patients and other indicators still have a large room for improvement even for the most preferred regimen recommended by many guidelines,atezolizumab plus bevacizumab.It is speculated that a large number of HCC patients are in a state of primary immunotherapy resistance,leading to tumor immune escape,which is closely related to tumor microenvironment and tumor internal factors.Recent studies have found that HCC patients have a wide range of microbial dysregulation,including intestinal flora and the intratumoral flora.The former may interact with immune cells in the tumor microenvironment through their lipopolysaccharide(LPS),bacterial metabolites(such as secondary bile acids and short-chain fatty acids)or their own structural proteins.The latter may change the biological characteristics of HCC cells and immune cells by regulating gene expressions at the epigenetic level and substance metabolites,thereby inducing immunosuppressive microenvironment and leading to immune escape of HCC.Here the characteristics of microbial dysregulation in HCC patients were summarized,and the potential mechanisms of HCC immune escape induced by intestinal flora and intratumoral flora were reviewed,in order to provide reference for the relationship between intestinal flora and immunotherapy resistance of HCC.

关 键 词：肝细胞癌 免疫逃逸 肿瘤微环境 菌群失调 

分 类 号：Q936[生物学—微生物学]