{"title":"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。","authors":"Huan Chen, Zhaofeng Xiao, Zhengyang Lu, Nan Xu, Qiang Wei, Xiao Xu","doi":"10.21147/j.issn.1000-9604.2025.02.08","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. <i>In vivo</i> 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.</p><p><strong>Conclusions: </strong>Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.</p>","PeriodicalId":9882,"journal":{"name":"Chinese Journal of Cancer Research","volume":"37 2","pages":"212-226"},"PeriodicalIF":7.0000,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062980/pdf/","citationCount":"0","resultStr":"{\"title\":\"Targeted activation of junctional adhesion molecule-like protein<b>+</b> CD8<b>+</b> T cells enhances immunotherapy in hepatocellular carcinoma.\",\"authors\":\"Huan Chen, Zhaofeng Xiao, Zhengyang Lu, Nan Xu, Qiang Wei, Xiao Xu\",\"doi\":\"10.21147/j.issn.1000-9604.2025.02.08\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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. <i>In vivo</i> 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.</p><p><strong>Conclusions: </strong>Activation of JAML enhances CTL responses in HCC treatment, independent of αPD-L1-mediated immunotherapy, providing a promising strategy for advanced HCC.</p>\",\"PeriodicalId\":9882,\"journal\":{\"name\":\"Chinese Journal of Cancer Research\",\"volume\":\"37 2\",\"pages\":\"212-226\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2025-04-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12062980/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chinese Journal of Cancer Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.21147/j.issn.1000-9604.2025.02.08\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chinese Journal of Cancer Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.21147/j.issn.1000-9604.2025.02.08","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
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.
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.