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Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis

Oncogene volume 43, pages 2635–2646 (2024)Cite this article

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Abstract

Gastric cancer (GC) is a substantial global health concern, and the development of liver metastasis (LM) in GC represents a critical stage linked to unfavorable patient prognoses. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the immune landscape of GC liver metastasis, revealing several immuno-suppressive components within the tumor immune microenvironment (TIM). Our findings unveiled an increased presence of cancer-associated fibroblasts (CAFs), myeloid-derived suppressor cell (MDSC)-like macrophages, tumor-associated macrophage (TAM)-like macrophages, and naive T cells, while conventional dendritic cells (cDCs) and effector CD8 T cells declined in LM. Additionally, we identified two distinct natural killer (NK) cell clusters exhibiting differential cytotoxicity-related gene expression, with cytotoxic NK cells notably reduced in LM. Strikingly, TGFβ was identified as an inducer of NK cell dysfunction, potentially contributing to immune evasion and tumor metastasis. In preclinical LM models, the combined approach of inhibiting TGFβ and transferring NK cells exhibited a synergistic impact, resulting in a significant reduction in liver metastasis. This work highlights the importance of understanding the complex immune dynamics within GC liver metastasis and presents a promising strategy combining TGFβ inhibition and NK-based immunotherapy to improve patient outcomes.

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Fig. 1: Single-cell transcriptome map of cell types in HL, GC, and LM specimens.
Fig. 2: Characterization and dynamic of the endothelial/fibroblast lineage.
Fig. 3: Altered myeloid populations in liver metastasis of gastric cancer.
Fig. 4: Characterization of T cell subclusters in liver metastasis of gastric cancer.
Fig. 5: Characterization of two distinct NK cell clusters in liver metastasis of gastric cancer.
Fig. 6: Enhanced cell-cell communication, TGFβ signaling, and therapeutic targeting in gastric cancer liver metastasis.

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Data availability

The scRNA-seq data presented in this study have been submitted to the GEO database and are available under accession number GSE246662. All codes and scripts used for association studies are available on request.

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Acknowledgements

We thank the Research Center for Basic Medical Sciences of Qilu Hospital for experimental supporting in this article.

Funding

This study was supported by grants from the National Natural Science Foundation of China [Nos. 82373000, 82203634], and the Natural Science Foundation of Shandong Province [No. ZR2021MH344]. The funding bodies had no role in the design of the study and collection, analysis, and interpretation of data and writing of this manuscript.

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  1. These authors contributed equally: Xiaolong Tang, Lei Gao.

Authors and Affiliations

  1. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China

    Xiaolong Tang, Lei Gao, Zhenyu Hou & Hui Qu

  2. Department of Clinical Medicine, Qilu Medical College of Shandong University, Jinan, 250011, China

    Xingzhi Jiang, Yiwen Wang & Shiyang Hou

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Contributions

HQ and XLT designed this study and experiments. XLT, LG, XZJ, and SYH performed the experiments. XLT, ZYH, and YWW analyzed the data and wrote the manuscript. HQ reviewed and supervised the manuscript. All authors contributed to experimental design and data analysis. The author(s) read and approved the final manuscript.

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Correspondence to Hui Qu.

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The authors declare no competing interests.

Ethics approval and consent to participate

The study was performed in accordance with the Declaration of Helsinki. The research protocol has been approved by the Ethical Committee of the School of Basic Medical Sciences, Shandong University [Document No. KYLL-2023(ZM)-036], with informed consent obtained from all participants. The authors have obtained informed consent for the publication of the patients’ images.

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Tang, X., Gao, L., Jiang, X. et al. Single-cell profiling reveals altered immune landscape and impaired NK cell function in gastric cancer liver metastasis. Oncogene 43, 2635–2646 (2024). https://doi.org/10.1038/s41388-024-03114-0

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