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

Author:

Mao Chenchen12,Chen Yanyu23,Xing Dong2,Zhang Teming2,Mei Dianfeng2,Han Zheng2,Xie Wangkai2,Long Cong2,Lin Yangxuan4,Yu Jiaye2,Xiang Dan2,Lu Mingdong1,Shen Xian5,Xue Xiangyang12ORCID

Affiliation:

1. Department of General Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University

2. Department of Microbiology and Immunology, Institute of Molecular Virology and Immunology, School of Basic Medical Sciences, Wenzhou Medical University

3. Department of Pediatric Thoracic Surgery, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University

4. Department of Thoracic Surgery, The First Affiliated Hospital of Wenzhou Medical University

5. Department of General Surgery, The First Affiliated Hospital of Wenzhou Medical University

Abstract

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.

Publisher

eLife Sciences Publications, Ltd

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