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
{"title":"CXCL12+肿瘤相关内皮细胞增强肝细胞癌的免疫抵抗力","authors":"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","doi":"10.1016/j.jhep.2024.09.044","DOIUrl":null,"url":null,"abstract":"<h3>Background</h3>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.<h3>Methods</h3>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.<h3>Results</h3>In this research, we identified a new subset of CXCL12<sup>+</sup> TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12<sup>+</sup> TECs impede the differentiation of CD8<sup>+</sup> naïve T cells into CD8<sup>+</sup> 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.<h3>Conclusions</h3>CXCL12<sup>+</sup> TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12<sup>+</sup> TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.<h3>Impact and implication</h3>This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12<sup>+</sup> TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12<sup>+</sup> TECs as inhibitors of CD8<sup>+</sup> 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.","PeriodicalId":15888,"journal":{"name":"Journal of Hepatology","volume":null,"pages":null},"PeriodicalIF":26.8000,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"CXCL12+ Tumor-associated Endothelial Cells Promote Immune Resistance in Hepatocellular Carcinoma.\",\"authors\":\"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\",\"doi\":\"10.1016/j.jhep.2024.09.044\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<h3>Background</h3>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.<h3>Methods</h3>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.<h3>Results</h3>In this research, we identified a new subset of CXCL12<sup>+</sup> TECs that exert a crucial role in immune suppression within the HCC TME. Functionally, CXCL12<sup>+</sup> TECs impede the differentiation of CD8<sup>+</sup> naïve T cells into CD8<sup>+</sup> 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.<h3>Conclusions</h3>CXCL12<sup>+</sup> TECs are pivotal in mediating immunosuppression within HCC microenvironment and targeting CXCL12<sup>+</sup> TECs presents a promising approach to augment the efficacy of immunotherapies in HCC patients.<h3>Impact and implication</h3>This investigation reveals a pivotal mechanism in the HCC TME, where CXCL12<sup>+</sup> TECs emerge as crucial modulators of immune suppression. The discovery of CXCL12<sup>+</sup> TECs as inhibitors of CD8<sup>+</sup> 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.\",\"PeriodicalId\":15888,\"journal\":{\"name\":\"Journal of Hepatology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":26.8000,\"publicationDate\":\"2024-10-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Hepatology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jhep.2024.09.044\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Hepatology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jhep.2024.09.044","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
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.
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.