{"title":"分割GlcNAc可通过抑制PD-L1的表达及其与PD-1的结合来增强CD8+ T细胞介导的乳腺癌杀伤。","authors":"Xueting Ren, Jinpeng Wu, Jing Li, Zhen Zhai, Xiang Li, Feng Guan, Meng Wang, Xiaobin Ma, Zengqi Tan, Huafeng Kang, Shuai Lin","doi":"10.1186/s40164-025-00693-w","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.</p><p><strong>Methods: </strong>This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8<sup>+</sup> T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.</p><p><strong>Results: </strong>MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8<sup>+</sup> T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8<sup>+</sup> T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs' ability to block CD8<sup>+</sup> T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8<sup>+</sup> T cell abundance and activity, achieving a more effective antitumor response in vivo.</p><p><strong>Conclusions: </strong>These findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8<sup>+</sup> T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.</p>","PeriodicalId":12180,"journal":{"name":"Experimental Hematology & Oncology","volume":"14 1","pages":"102"},"PeriodicalIF":13.5000,"publicationDate":"2025-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323189/pdf/","citationCount":"0","resultStr":"{\"title\":\"Bisecting GlcNAc enhances CD8<sup>+</sup> T cell-mediated killing of breast cancer by suppressing PD-L1 expression and its binding to PD-1.\",\"authors\":\"Xueting Ren, Jinpeng Wu, Jing Li, Zhen Zhai, Xiang Li, Feng Guan, Meng Wang, Xiaobin Ma, Zengqi Tan, Huafeng Kang, Shuai Lin\",\"doi\":\"10.1186/s40164-025-00693-w\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.</p><p><strong>Methods: </strong>This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8<sup>+</sup> T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.</p><p><strong>Results: </strong>MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8<sup>+</sup> T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8<sup>+</sup> T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs' ability to block CD8<sup>+</sup> T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8<sup>+</sup> T cell abundance and activity, achieving a more effective antitumor response in vivo.</p><p><strong>Conclusions: </strong>These findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8<sup>+</sup> T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.</p>\",\"PeriodicalId\":12180,\"journal\":{\"name\":\"Experimental Hematology & Oncology\",\"volume\":\"14 1\",\"pages\":\"102\"},\"PeriodicalIF\":13.5000,\"publicationDate\":\"2025-08-04\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12323189/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental Hematology & Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1186/s40164-025-00693-w\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental Hematology & Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40164-025-00693-w","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
Bisecting GlcNAc enhances CD8+ T cell-mediated killing of breast cancer by suppressing PD-L1 expression and its binding to PD-1.
Background: The abundance of PD-L1 on the surface of tumor cells is a critical factor in sensitizing these cells to T cell-mediated immune killing. While abnormal glycosylation of PD-L1 is known to influence its expression and function, the precise regulatory mechanisms remain unclear.
Methods: This study utilized bioinformatics analysis to explore the role of MGAT3, a key gene involved in the formation of the bisecting GlcNAc structure, in breast cancer (BC). Experimental approaches were employed to increase bisecting GlcNAc levels in BC cells, followed by assessments of PD-L1 expression, CD8+ T cell-mediated cytotoxicity, extracellular vesicle (EV)-associated PD-L1, and PD-L1/PD-1 interaction. Additionally, forskolin, a bisecting GlcNAc agonist, was combined with anti-PD-L1 antibody to evaluate its antitumor effects in vivo.
Results: MGAT3 was found to be expressed at low levels in BC tissues but positively correlated with CD8+ T cell infiltration. Elevating bisecting GlcNAc levels in BC cells significantly enhanced the cytotoxic efficacy of CD8+ T cells. High bisecting GlcNAc modification promoted PD-L1 degradation via the lysosomal pathway, reducing PD-L1 expression and its binding to PD-1. Furthermore, increased bisecting GlcNAc levels reduced PD-L1 in tumor cell-derived EVs, impairing the EVs' ability to block CD8+ T cells and indirectly enhancing T cell cytotoxicity. The combined use of forskolin and anti-PD-L1 antibody significantly increased CD8+ T cell abundance and activity, achieving a more effective antitumor response in vivo.
Conclusions: These findings demonstrate that enhancing bisecting GlcNAc modification in BC cells promotes PD-L1 degradation and inhibits its binding to PD-1, thereby boosting CD8+ T cell-mediated cytotoxicity, providing a promising strategy for immune modulation in BC therapy.
期刊介绍:
Experimental Hematology & Oncology is an open access journal that encompasses all aspects of hematology and oncology with an emphasis on preclinical, basic, patient-oriented and translational research. The journal acts as an international platform for sharing laboratory findings in these areas and makes a deliberate effort to publish clinical trials with 'negative' results and basic science studies with provocative findings.
Experimental Hematology & Oncology publishes original work, hypothesis, commentaries and timely reviews. With open access and rapid turnaround time from submission to publication, the journal strives to be a hub for disseminating new knowledge and discussing controversial topics for both basic scientists and busy clinicians in the closely related fields of hematology and oncology.