Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate PoorOutcomein Hepatocellular Carcinoma
Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate PoorOutcomein Hepatocellular Carcinoma
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激活和耗尽的 MAIT 细胞促进疾病进展并表明肝细胞癌的预后不佳
DOI：
10.1158/1078-0432.ccr-18-3040
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发表时间：
2019-06-01
影响因子：
11.5
通讯作者：
Gao, Qiang
中科院分区：
文献类型：
--
作者：
Duan, Meng;Goswami, Shyamal;Gao, Qiang
目的：先天免疫是肿瘤免疫监测不可或缺的一环，肝脏是先天免疫占优势的器官，其粘膜相关不变性T （MAIT）细胞富集。然而，人们对MAIT细胞在肝细胞癌（HCC）中的表型、功能和免疫调节作用知之甚少。实验设计：通过流式细胞术（FCM）和体外生物测定法评估肝癌患者MAIT细胞的分布、表型和功能。对MAIT细胞进行转录组学分析。肿瘤浸润MAIT细胞的预后意义在四个独立的HCC患者队列中得到验证。结果：尽管MAIT细胞在HCC肿瘤中的密度低于正常肝脏，但与其他粘膜相关器官相比，MAIT细胞在HCC微环境中显著富集。肿瘤来源的MAIT细胞表现出典型的CCR7(+) CD45RA(+) CD45RO(+) CD95（+）效应记忆表型，具有较低的共刺激和效应能力。肿瘤诱导的mait细胞显著上调PD-1、CTLA-4、TIM-3等抑制分子，显著减少IFNg和il - 17的分泌，减少颗粒酶B和perforin的产生，同时转向产生il - 8等促肿瘤细胞因子。转录组测序证实，肿瘤源性MAIT细胞通过下调细胞因子分泌和细胞溶解效应功能通路中富集的基因（如enfkb1和STAT5B）以及上调IL8、CXCL12和HAVCR2 （TIM-3）等基因，向肿瘤促进方向重编程。FCM、qRT-PCR和多重免疫组化分析分别显示，HCC中MAIT细胞的高浸润与不良临床预后显著相关。结论：hcc浸润的MAIT细胞功能受损，甚至重编程，从抗肿瘤免疫转向促肿瘤方向。
Purpose: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions, and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC).Experimental Design: The distribution, phenotype, and function of MAIT cells in patients with HCC were evaluated by both flow cytometry (FCM) and in vitro bioassays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of patients with HCC.Results: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosaassociated organs. Tumor-derived MAIT cells displayed a typical CCR7(+) CD45RA(+) CD45RO(+) CD95(+) effector memory phenotype with lower costimulatory and effector capabilities. Tumor-educatedMAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, secreted significantly less IFNg and IL17, andproducedminimal granzyme B and perforin while shifting to produce tumor-promoting cytokines like IL8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction by downregulating genes enriched in pathways of cytokine secretionand cytolysis effector function likeNFKB1 and STAT5B and by upregulating genes like IL8, CXCL12, and HAVCR2 (TIM-3). High infiltration of MAIT cells in HCC significantly correlated with an unfavorable clinical outcome, revealed by FCM, qRT-PCR, and multiplex IHC analyses, respectively.Conclusions: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.