Reprogramming CD8+ T-cell Branched N-Glycosylation Limits Exhaustion, Enhancing Cytotoxicity and Tumor Killing
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| Název: | Reprogramming CD8+ T-cell Branched N-Glycosylation Limits Exhaustion, Enhancing Cytotoxicity and Tumor Killing |
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| Autoři: | Catarina M. Azevedo, Bingxian Xie, William G. Gunn, Ronal M. Peralta, Carolina S. Dantas, Henrique Fernandes-Mendes, Supriya Joshi, Victoria Dean, Pedro Almeida, Drew Wilfahrt, Nuno Mendes, Julian López Portero, Carmen Poves, María Jesús Fernández-Aceñero, Ricardo Marcos-Pinto, Ângela Fernandes, Greg M. Delgoffe, Salomé S. Pinho |
| Přispěvatelé: | Instituto de Investigação e Inovação em Saúde |
| Zdroj: | Cancer Immunology Research. 13:1655-1673 |
| Informace o vydavateli: | American Association for Cancer Research (AACR), 2025. |
| Rok vydání: | 2025 |
| Témata: | Colorectal Neoplasms/ immunology, Cytotoxicity, Immunologic, Colorectal Neoplasms/ therapy, Glycosylation, CD8-Positive T-Lymphocytes/ immunology, N-Acetylglucosaminyltransferases / metabolism, CD8-Positive T-Lymphocytes/ metabolism, Mice, Cell Line, Tumor, Polysaccharides / metabolism, Colorectal Neoplasms/ metabolism, Animals, Humans, Immunotherapy, Adoptive / methods, Colorectal Neoplasms/ pathology, N-Acetylglucosaminyltransferases / genetics |
| Popis: | T-cell therapies have transformed cancer treatment. Although surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell–mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc–branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR-Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted the assessment of whether MGAT5 deletion in anti-CD19 chimeric antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 knockout anti-CD19–CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance the antitumor activity of native and CAR T cells. |
| Druh dokumentu: | Article |
| Popis souboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 2326-6074 2326-6066 |
| DOI: | 10.1158/2326-6066.cir-25-0313 |
| Přístupová URL adresa: | https://hdl.handle.net/10216/169503 |
| Přístupové číslo: | edsair.doi.dedup.....6e5f6f26c905966428cb0ac904027b11 |
| Databáze: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstrakt: | T-cell therapies have transformed cancer treatment. Although surface glycans have been shown to play critical roles in regulating T-cell development and function, whether and how the glycome influences T cell–mediated tumor immunity remains an area of active investigation. In this study, we show that the intratumoral T-cell glycome is altered early in human colorectal cancer, with substantial changes in branched N-glycans. We demonstrated that CD8+ T cells expressing β1,6-GlcNAc–branched N-glycans adopted an exhausted phenotype, marked by increased PD1 and Tim3 expression. CRISPR-Cas9 deletion of key branching glycosyltransferase genes revealed that Mgat5 played a prominent role in T-cell exhaustion. In culture-based assays and tumor studies, Mgat5 deletion in CD8+ T cells resulted in improved cancer cell killing. These findings prompted the assessment of whether MGAT5 deletion in anti-CD19 chimeric antigen receptor (CAR) T cells could enable this therapeutic modality in a solid tumor setting. We showed that MGAT5 knockout anti-CD19–CAR T cells inhibited the growth of CD19-transduced tumors. Together, these findings show that MGAT5-mediated branched N-glycans regulate CD8+ T-cell function in cancer and provide a strategy to enhance the antitumor activity of native and CAR T cells. |
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| ISSN: | 23266074 23266066 |
| DOI: | 10.1158/2326-6066.cir-25-0313 |