https://scholars.lib.ntu.edu.tw/handle/123456789/637023
標題: | Targeting tumor O-glycosylation modulates cancer-immune-cell crosstalk and enhances anti-PD-1 immunotherapy in head and neck cancer | 作者: | MEI-CHUN LIN Chuang, Ya-Ting Hsin-Yi Wu CHIA-LANG HSU NENG-YU LIN MIN-CHUAN HUANG PEI-JEN LOU |
關鍵字: | IL-6; O-glycosylation; core 1 β1,3-galactosyltransferase; head and neck cancer; immune checkpoint inhibitor; itraconazole | 公開日期: | 2024 | 卷: | 18 | 期: | 2 | 起(迄)頁: | 350 | 來源出版物: | Molecular oncology | 摘要: | Cells in the tumor microenvironment (TME) communicate via membrane-bound and secreted proteins, which are mostly glycosylated. Altered glycomes of malignant tumors influence behaviors of stromal cells. In this study, we showed that the loss of core-1 β1,3-galactosyltransferase (C1GALT1)-mediated O-glycosylation suppressed tumor growth in syngeneic head and neck cancer mouse models. O-glycan truncation in tumor cells promoted the M1 polarization of macrophages, enhanced T-cell-mediated cytotoxicity, and reduced interleukin-6 (IL-6) levels in the secretome. Proteasomal degradation of IL-6 was controlled by the O-glycan at threonine 166. Both IL-6/IL-6R blockade and O-glycan truncation in tumor cells induced similar pro-inflammatory phenotypes in macrophages and cytotoxic T lymphocytes (CTLs). The combination of the O-glycosylation inhibitor itraconazole and anti-programmed cell death protein 1 (anti-PD-1) antibody effectively suppressed tumor growth in vivo. Collectively, our findings demonstrate that O-glycosylation in tumor cells governs their crosstalk with macrophages and CTLs. Thus, targeting O-glycosylation successfully reshapes the TME and consequently enhances the efficacy of anti-PD-1 therapy. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/637023 | ISSN: | 15747891 | DOI: | 10.1002/1878-0261.13489 |
顯示於: | 醫學系 |
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