{"title":"DAB2 + 巨噬细胞支持 FAP + 成纤维细胞形成肿瘤屏障,并诱发肝癌的不良临床预后。","authors":"Fei Long, Wei Zhong, Faming Zhao, Yaqi Xu, Xin Hu, Gaihua Jia, Lanxiang Huang, Kezhen Yi, Na Wang, Huaqi Si, Jun Wang, Bicheng Wang, Yuan Rong, Yufeng Yuan, Chunhui Yuan, Fubing Wang","doi":"10.7150/thno.99046","DOIUrl":null,"url":null,"abstract":"<p><p><b>Background:</b> Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. <b>Methods:</b> A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. <b>Results:</b> Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). <i>FAP</i> <sup>+</sup> fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The <i>DAB2</i> <sup>+</sup> and <i>SPP1</i> <sup>+</sup> tumor-associated macrophages (TAMs) reinforce the function of <i>FAP</i> <sup>+</sup> CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between <i>DAB2</i> <sup>+</sup> TAMs and <i>FAP</i> <sup>+</sup> CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. <b>Conclusions:</b> The interaction between <i>DAB2</i> <sup>+</sup> TAMs and <i>FAP</i> <sup>+</sup> CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of <i>FAP</i> <sup>+</sup> CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":null,"pages":null},"PeriodicalIF":12.4000,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373629/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>DAB2</i> <sup>+</sup> macrophages support <i>FAP</i> <sup>+</sup> fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.\",\"authors\":\"Fei Long, Wei Zhong, Faming Zhao, Yaqi Xu, Xin Hu, Gaihua Jia, Lanxiang Huang, Kezhen Yi, Na Wang, Huaqi Si, Jun Wang, Bicheng Wang, Yuan Rong, Yufeng Yuan, Chunhui Yuan, Fubing Wang\",\"doi\":\"10.7150/thno.99046\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Background:</b> Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. <b>Methods:</b> A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. <b>Results:</b> Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). <i>FAP</i> <sup>+</sup> fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The <i>DAB2</i> <sup>+</sup> and <i>SPP1</i> <sup>+</sup> tumor-associated macrophages (TAMs) reinforce the function of <i>FAP</i> <sup>+</sup> CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between <i>DAB2</i> <sup>+</sup> TAMs and <i>FAP</i> <sup>+</sup> CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. <b>Conclusions:</b> The interaction between <i>DAB2</i> <sup>+</sup> TAMs and <i>FAP</i> <sup>+</sup> CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of <i>FAP</i> <sup>+</sup> CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.</p>\",\"PeriodicalId\":22932,\"journal\":{\"name\":\"Theranostics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.4000,\"publicationDate\":\"2024-08-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373629/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Theranostics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.7150/thno.99046\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.99046","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
DAB2+ macrophages support FAP+ fibroblasts in shaping tumor barrier and inducing poor clinical outcomes in liver cancer.
Background: Cancer-associated fibroblasts (CAFs) are the key components of the immune barrier in liver cancer. Therefore, gaining a deeper understanding of the heterogeneity and intercellular communication of CAFs holds utmost importance in boosting immunotherapy effectiveness and improving clinical outcomes. Methods: A comprehensive analysis by combing single-cell, bulk, and spatial transcriptome profiling with multiplexed immunofluorescence was conducted to unravel the complexities of CAFs in liver cancer. Results: Through an integrated approach involving 235 liver cancer scRNA-seq samples encompassing over 1.2 million cells, we found that CAFs were particularly increased in hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). FAP+ fibroblasts were identified as the dominant subtype of CAFs, and which were mainly involved in extracellular matrix organization and angiogenesis. These CAFs were enriched in the tumor boundary of HCC, but diffusely scattered within ICC. The DAB2+ and SPP1+ tumor-associated macrophages (TAMs) reinforce the function of FAP+ CAFs through signals such as TGF-β, PDGF, and ADM. Notably, the interaction between DAB2+ TAMs and FAP+ CAFs promoted the formation of immune barrier and correlated with poorer patient survival, non-response to immunotherapy in HCC. High FAP and DAB2 immunohistochemical scores predicted shorter survival and higher serum AFP concentration in a local clinical cohort of 90 HCC patients. Furthermore, this communication pattern might be applicable to other solid malignancies as well. Conclusions: The interaction between DAB2+ TAMs and FAP+ CAFs appears crucial in shaping the immune barrier. Strategies aimed at disrupting this communication or inhibiting the functions of FAP+ CAFs could potentially enhance immunotherapy effectiveness and improve clinical outcomes.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.