靶向激活连接粘附分子样蛋白+ CD8+ T细胞增强肝癌的免疫治疗。

IF 7 2区 医学 Q1 ONCOLOGY
Huan Chen, Zhaofeng Xiao, Zhengyang Lu, Nan Xu, Qiang Wei, Xiao Xu
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引用次数: 0

摘要

目的:细胞毒性T淋巴细胞(ctl)在肝细胞癌(HCC)的治疗中起着至关重要的作用。最近的研究表明,连接粘附分子样蛋白(JAML)可增强CD8+ T细胞的抗肿瘤活性。我们的研究探讨了JAML+ CD8+ T细胞在HCC中的作用。方法:我们使用飞行时间细胞术和原位肝癌小鼠模型来检测接受免疫治疗的肿瘤浸润免疫细胞的组蛋白修饰。流式细胞术检测CD4+ T细胞在浸润性HCC中的分化及JAML表达。相关分析显示,乳酸脱氢酶a + (LDHA+) CD4+ T细胞与JAML+ CD8+ T细胞呈正相关。随后,我们评估了一种激动性抗jaml抗体单独或联合免疫治疗的治疗效果。最后,进行RNA测序以确定潜在的调控机制。结果:免疫治疗显著增加CD8+ T细胞浸润HCC的百分比,并诱导组蛋白修饰,如CD4+ T细胞中的H3K18乳酸化(H3K18la)。流式细胞术分析显示,乳酸促进CD4+ T细胞向Th1细胞分化。LDHA是一种将丙酮酸转化为乳酸的酶,在这一过程中起着关键作用。相关分析显示,在免疫治疗应答的患者中,LDHA+ CD4+ T细胞和JAML+ CD8+ T细胞呈正相关。此外,CD8+ T细胞中JAML的高表达与更有利的预后相关。体内实验表明,在不依赖于抗程序性细胞死亡蛋白配体-1抗体(αPD-L1)介导的免疫治疗的情况下,拮抗jaml抗体治疗可减少荷瘤小鼠的肿瘤体积,显著延长荷瘤小鼠的生存期。途径富集分析进一步揭示了JAML通过氧化磷酸化途径增强CTL反应。结论:激活JAML可增强HCC治疗中的CTL反应,不依赖于α pd - l1介导的免疫治疗,为晚期HCC治疗提供了一种有希望的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeted activation of junctional adhesion molecule-like protein+ CD8+ T cells enhances immunotherapy in hepatocellular carcinoma.

Objective: Cytotoxic T lymphocytes (CTLs) play a crucial role in the therapeutic approach to hepatocellular carcinoma (HCC). Recent research has indicated that junctional adhesion molecule-like protein (JAML) enhances the antitumor activity of CD8+ T cells. Our study investigates the role of JAML+ CD8+ T cells in HCC.

Methods: We utilized time-of-flight mass cytometry and an orthotopic mouse model of HCC to examine histone modifications in tumor-infiltrating immune cells undergoing immunotherapy. Flow cytometry was used to assess CD4+ T cells differentiation and JAML expression in CD8+ T cells infiltrating HCC. Correlation analysis revealed a strong positive correlation between lactate dehydrogenase A+ (LDHA+) CD4+ T cells and JAML+ CD8+ T cells. Subsequently, we evaluated the therapeutic effects of an agonistic anti-JAML antibody, both alone and combined with immunotherapy. Finally, RNA sequencing was conducted to identify potential regulatory mechanisms.

Results: Immunotherapy significantly increased the percentage of CD8+ T cells infiltrating HCC and induced histone modifications, such as H3K18 lactylation (H3K18la) in CD4+ T cells. Flow cytometry analysis revealed that lactate promotes the differentiation of CD4+ T cells into Th1 cells. LDHA, an enzyme that converts pyruvate to lactate, plays a key role in this process. Correlation analysis revealed a strong positive relationship between LDHA+ CD4+ T cells and JAML+ CD8+ T cells in patients who responded to immunotherapy. Moreover, high JAML expression in CD8+ T cells was associated with a more favorable prognosis. In vivo experiments demonstrated that agonistic anti-JAML antibody therapy reduced tumor volume and significantly prolonged the survival of tumor-bearing mice, independent of the effects of anti-programmed cell death protein ligand-1 antibody (αPD-L1)-mediated immunotherapy. Pathway enrichment analysis further revealed that JAML enhances CTL responses through the oxidative phosphorylation pathway.

Conclusions: Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.

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来源期刊
自引率
9.80%
发文量
1726
审稿时长
4.5 months
期刊介绍: Chinese Journal of Cancer Research (CJCR; Print ISSN: 1000-9604; Online ISSN:1993-0631) is published by AME Publishing Company in association with Chinese Anti-Cancer Association.It was launched in March 1995 as a quarterly publication and is now published bi-monthly since February 2013. CJCR is published bi-monthly in English, and is an international journal devoted to the life sciences and medical sciences. It publishes peer-reviewed original articles of basic investigations and clinical observations, reviews and brief communications providing a forum for the recent experimental and clinical advances in cancer research. This journal is indexed in Science Citation Index Expanded (SCIE), PubMed/PubMed Central (PMC), Scopus, SciSearch, Chemistry Abstracts (CA), the Excerpta Medica/EMBASE, Chinainfo, CNKI, CSCI, etc.
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