Lu Yajie, Liu Yunpeng, Zuo Xiaoshuang, Li Guodong, Wang Jianlin, Liu Jianshan, Wang Xiangxu, Wang Shuning, Zhang Wangqian, Zhang Kuo, Lei Xiaoying, Hao Qiang, Li Weina, Liu Lei, Li Meng, Zhang Cun, Zhang Hong-Mei, Zhang Yingqi, Gao Yuan
State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China; Innovation Research Institute, Xijing Hospital, Air Force Medical University, 710032 Xi'an, People's Republic of China.
The Department of Clinical Oncology, Xijing Hospital, The Fourth Military Medical University, 710032 Xi'an, People's Republic of China.
J Hepatol. 2025 Apr;82(4):634-648. doi: 10.1016/j.jhep.2024.09.044. Epub 2024 Oct 9.
BACKGROUND & AIMS: 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.
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 patients with HCC, 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.
In this study, 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.
CXCL12 TECs are pivotal in mediating immunosuppression within the HCC microenvironment and targeting CXCL12 TECs presents a promising approach to augment the efficacy of immunotherapies in patients with HCC.
This investigation reveals a pivotal mechanism wherein CXCL12 tumor-associated endothelial cells (TECs) emerge as crucial modulators of immune suppression in the tumor microenvironment of hepatocellular carcinoma (HCC). The discovery of CXCL12 TECs as inhibitors of CD8 naïve T cell activation and recruiters of myeloid-derived suppressor cells 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.
肿瘤微环境（TME）在肝细胞癌（HCC）现有治疗效果有限中起着关键作用，肿瘤相关内皮细胞（TECs）作为TME的基本组成部分，对肿瘤进展和治疗效果有重大影响。然而，TECs在HCC中的精确作用和机制仍未得到充分了解。
我们采用多组学分析策略来研究HCC肿瘤微环境中TECs的单细胞和时空演变，展示其对免疫治疗的不同反应。通过对HCC患者临床队列的分析，我们探索了TEC亚群与免疫治疗结果之间的相关性。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亚群在微环境调节中的机制及其对免疫治疗的影响，我们利用了TEC亚群特异性敲除小鼠模型以及人源化小鼠模型。
在本研究中，我们鉴定出一种新的CXCL12 TECs亚群，其在HCC TME的免疫抑制中发挥关键作用。在功能上，CXCL12 TECs通过分泌CXCL12阻碍CD8初始T细胞分化为CD8细胞毒性T细胞。此外，它们吸引髓系来源的抑制细胞（MDSCs）。开发了一种双特异性抗体，专门靶向CXCL12和PD1，在增强抗肿瘤免疫反应和推进HCC治疗方面显示出巨大潜力。
CXCL12 TECs在介导HCC微环境中的免疫抑制方面至关重要，靶向CXCL12 TECs是提高HCC患者免疫治疗疗效的一种有前景的方法。
本研究揭示了一种关键机制，即CXCL12肿瘤相关内皮细胞（TECs）成为肝细胞癌（HCC）肿瘤微环境中免疫抑制的关键调节因子。CXCL12 TECs作为CD8初始T细胞激活抑制剂和髓系来源抑制细胞招募者的发现，显著推进了我们对HCC与免疫调节之间动态关系的理解。此外，精确靶向CXCL12和PD1的双特异性抗体的开发和应用，已证明在人源化小鼠HCC模型中增强了免疫反应。这一发现强调了HCC一个有前景的治疗方向，有可能扩大当前免疫治疗的影响。
