
静止状態の自然キラー細胞は、腫瘍由来のsoluble stem cell factor (sSCF)の上昇を介して、大腸がん肝転移の悪性化を促進する。


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Purpose 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)

Methods 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.

Results 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.

Conclusion 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.

### Competing Interest Statement

The authors have declared no competing interest.

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

大腸がん肝転移の進行を促進する静止状態の自然キラー細胞