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Resting natural killer cells promote the progress of colon cancer liver metastasis by elevating tumor-derived sSCF

转移 癌症研究 生物 淋巴因子激活杀伤细胞 转录组 细胞 癌症 癌细胞 肿瘤微环境 自然杀伤细胞 体外 免疫学 免疫系统 白细胞介素21 细胞毒性T细胞 基因表达 T细胞 基因 肿瘤细胞 生物化学 遗传学
作者
Chenchen Mao,Yanyu Chen,Dong Xing,Teming Zhang,Dianfeng Mei,Zheng Han,Wangkai Xie,Cong Long,Yongjuan Lin,Jiaye Yu,Dan Xiang,Mingdong Lu,Xian Shen,Xiangyang Xue
标识
DOI:10.7554/elife.97201
摘要

The abundance and biological contribution of Natural killer (NK) cells in cancer are controversial. Here, we aim to uncover clinical relevance and cellular roles of NK cells in colon cancer liver metastasis (CCLM)We integrated single-cell RNA sequencing, spatial transcriptomics, and bulk RNA-sequencing datasets to investigate NK cells’ biological properties and functions in the microenvironment of primary and liver metastatic tumors. Results were validated through an in vitro co-culture experiment based on bioinformatics analysis.We used single-cell RNA sequencing and spatial transcriptomics to map the immune cellular landscape of colon cancer and well-matched liver metastatic cancer. We discovered that GZMK+ resting NK cells increased significantly in tumor tissues and were enriched in the tumor regions of both diseases. After combining bulk RNA and clinical data, we observed that these NK cell subsets contributed to a worse prognosis. Meanwhile, KIR2DL4+ activated NK cells exhibited the opposite position and relevance. Pseudotime cell trajectory analysis revealed the evolution of activated to resting NK cells. In vitro experiments further confirmed that tumor-cell-co-cultured NK cells exhibited a resting status, as evidenced by decreased KIR2DL4 expression. Functional experiments finally revealed that NK cells exhibited tumor-activating characteristics by promoting the dissociation and release of SCF on the tumor cells membrane depending on cell-to-cell interaction, as the supernatant of the co-culture system enhanced tumor progression.Together, our findings revealed a population of protumorigenic NK cells that may be exploited for novel therapeutic strategies to improve therapeutic outcomes for patients with CCLM.
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