CXCL12+肿瘤相关内皮细胞增强肝细胞癌的免疫抵抗力

IF 26.8 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Journal of Hepatology Pub Date : 2024-10-09 DOI:10.1016/j.jhep.2024.09.044
Yajie Lu, Yunpeng Liu, Xiaoshuang Zuo, Guodong Li, Jianlin Wang, Jianshan Liu, Xiangxu Wang, Shuning Wang, Wangqian Zhang, Kuo Zhang, Xiaoying Lei, Qiang Hao, Weina Li, Lei Liu, Meng Li, Cun Zhang, Hongmei Zhang, Yingqi Zhang, Yuan Gao
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引用次数: 0

摘要

背景肿瘤微环境(TME)在现有肝细胞癌(HCC)治疗方法的有限疗效中起着至关重要的作用,而肿瘤相关内皮细胞(TECs)是肿瘤微环境的基本组成部分,对肿瘤的进展和疗效有重大影响。我们采用多组学分析策略,研究了对免疫疗法有不同反应的HCC肿瘤微环境中TECs的单细胞和时空演变。通过分析 HCC 患者的临床队列,我们探索了 TEC 亚群与免疫疗法结果之间的相关性。通过全面的体外和体内研究,证实了TEC亚群对免疫微环境的影响。为了进一步探索不同 TEC 亚群在微环境调控中的作用机制及其对免疫治疗的影响,我们利用了 TEC 亚群特异性基因敲除小鼠模型和人源化小鼠模型。结果在这项研究中,我们发现了一个新的 CXCL12+ TEC 亚群,它们在 HCC TME 内的免疫抑制中发挥着关键作用。在功能上,CXCL12+ TECs通过分泌CXCL12阻碍CD8+幼稚T细胞分化为CD8+细胞毒性T细胞。此外,它们还能吸引髓源性抑制细胞(MDSCs)。我们开发出了一种双特异性抗体,可同时特异性地靶向 CXCL12 和 PD1,在增强抗肿瘤免疫反应和促进 HCC 治疗方面显示出了巨大的前景。结论CXCL12+ TECs 在介导 HCC 微环境中的免疫抑制方面起着关键作用,靶向 CXCL12+ TECs 是增强 HCC 患者免疫疗法疗效的一种很有前景的方法。影响和意义这项研究揭示了 HCC TME 中的一种关键机制,CXCL12+ TECs 在其中成为免疫抑制的关键调节因子。CXCL12+ TECs 是 CD8+ 幼稚 T 细胞活化的抑制剂和 MDSCs 的招募者,这一发现极大地推动了我们对 HCC 与免疫调节之间动态关系的了解。此外,在人源化小鼠 HCC 模型中,精确靶向 CXCL12 和 PD1 的双特异性抗体的开发和应用已被证明能增强免疫反应。这一发现强调了治疗 HCC 的一个有前途的方向,为扩大目前免疫疗法的影响提供了可能性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.

Background

The tumor microenvironment (TME) plays a crucial role in the limited efficacy of existing treatments for hepatocellular carcinoma (HCC), with tumor-associated endothelial cells (TECs) serving as fundamental TME components that substantially influence tumor progression and treatment efficacy. However, the precise roles and mechanisms of TECs in HCC remain inadequately understood.

Methods

We employed a multi-omics profiling strategy to investigate the single-cell and spatiotemporal evolution of TECs within the microenvironment of HCC tumors showcasing varied responses to immunotherapy. Through an analysis of a clinical cohort of HCC patients, we explored the correlation between TEC subpopulations and immunotherapy outcomes. The influence of TEC subsets on the immune microenvironment was confirmed through comprehensive in vitro and in vivo studies. To further explore the mechanisms of distinct TEC subpopulations in microenvironmental modulation and their impact on immunotherapy, we utilized TEC subset-specific knockout mouse models as well as humanized mouse models.

Results

In this research, we identified a new subset of CXCL12+ TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12+ TECs impede the differentiation of CD8+ naïve T cells into CD8+ cytotoxic T cells by secreting CXCL12. Furthermore, they attract myeloid-derived suppressor cells (MDSCs). A bispecific antibody was developed to target both CXCL12 and PD1 specifically, showing significant promise in bolstering anti-tumor immune responses and advancing HCC therapy.

Conclusions

CXCL12+ TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12+ TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.

Impact and implication

This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12+ TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12+ TECs as inhibitors of CD8+ naïve T cell activation and recruiters of MDSCs significantly advances our grasp of the dynamic between HCC and immune regulation. Moreover, the development and application of a bispecific antibody precisely targeting CXCL12 and PD1 has proven to enhance immune responses in a humanized mouse HCC model. This finding underscores a promising therapeutic direction for HCC, offering the potential to amplify the impact of current immunotherapies.
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来源期刊
Journal of Hepatology
Journal of Hepatology 医学-胃肠肝病学
CiteScore
46.10
自引率
4.30%
发文量
2325
审稿时长
30 days
期刊介绍: The Journal of Hepatology is the official publication of the European Association for the Study of the Liver (EASL). It is dedicated to presenting clinical and basic research in the field of hepatology through original papers, reviews, case reports, and letters to the Editor. The Journal is published in English and may consider supplements that pass an editorial review.
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