上海交通大学学报（医学版）2025，Vol.45Issue(11)：1466-1479,14.DOI:10.3969/j.issn.1674-8115.2025.11.006
CD10+中性粒细胞通过SELPLG-SELL通路促进黏膜恶性黑色素瘤CD8+T细胞耗竭
CD10+neutrophils promote CD8+T-cell depletion in mucosal malignant melanoma through the SELPG-SELL pathway
摘要
Abstract
Objective·To compare the immune microenvironment of mucosal malignant melanoma(MM)and cutaneous malignant melanoma(CM)using single-cell transcriptome analysis system,and to elucidate the key regulatory mechanism of CD8+T cell depletion in MM.Methods·A total of 36 531 cells from three treatment-naïve MM surgical specimens and three CM samples were subjected to single-cell RNA sequencing.Data pre-processing included batch correction,strict quality control(based on mitochondrial gene ratio and gene number screening),unsupervised clustering,and cell-type annotation(using established marker genes).Differential gene analysis(Wilcoxon test),gene set enrichment analysis[based on Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)databases],cell-cell interaction network analysis,and prognostic association analysis using.The Cancer Genome Atlas(TCGA)were used to comprehensively analyse the heterogeneity of MM and CM tumour immune microenvironment.Results·Compared with CM,the expression of cytotoxicity-related genes(GZMB,IFNG,etc.)in CD8+T cells in MM was reduced(P＜0.001),while the depletion markers(PDCD1,LAG3,etc.)were significantly up-regulated(P＜0.001).The proportion of depleted CD8+T cell subsets increased by nearly 6 times(CM:3.38%vs MM:19.26%,P＜0.010),and the terminal depletion score was higher.In addition,the level of neutrophil infiltration in the MM microenvironment was significantly higher than that in CM(CM:1.6%vs MM:34.1%,P=0.009),and single-cell analysis further divided it into five subgroups.Among them,the CD10+neutrophil subset(accounting for 23.52%of MM neutrophils)highly expressed pro-inflammatory molecules(S100A8/A9)and immunosuppressive molecules(MME/CD10,CD55),and the characteristic scores of myeloid-derived suppressor cells(MDSCs)in this subset were significantly higher than those of other subgroups.TCGA and MM cohort analyses further confirmed that the highly expressed genes of this subset were independently associated with poor prognosis(P=0.049),suggesting that this subset was involved in tumour immunosuppressive effects.Mechanistically,CD10+neutrophils interacted with depleted CD8+T cells through the SELPLG-SELL ligand-receptor pair,driving T-cell inactivation.Conclusion·Single-cell transcriptome sequencing was performed on MM clinical samples,and the single-cell immunomes of MM and CM were systematically compared,suggesting that CD10+neutrophils in MM induce CD8+T-cell terminal depletion through the SELPLG-SELL pathway.The molecular mechanism of MM immunotherapy tolerance was elucidated,providing a new strategy for targeting neutrophil-T cell interaction.关键词
黏膜恶性黑色素瘤/中性粒细胞/CD8+耗竭T细胞/单细胞转录组Key words
mucosal malignant melanoma/neutrophils/CD8+depleted T cells/single-cell transcriptome分类
医药卫生引用本文复制引用
HAO Meiling,MA Yanni,MA Xuhui,ZHANG Yanjie,ZENG Hanlin,CHEN Shanshuang..CD10+中性粒细胞通过SELPLG-SELL通路促进黏膜恶性黑色素瘤CD8+T细胞耗竭[J].上海交通大学学报（医学版）,2025,45(11):1466-1479,14.基金项目
国家自然科学基金(82204421,82072638) （82204421,82072638）
上海市中央引导地方科技发展基金(YDZX20223100003007). National Natural Science Foundation of China(82204421,82072638) （YDZX20223100003007）
Shanghai Central Government-Guided Local Science and Technology Development Fund(YDZX20223100003007). （YDZX20223100003007）
