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ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases

Oncogene (2024)Cite this article

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Abstract

Gastric carcinoma (GC) is regarded as one of the deadliest cancer characterized by diversity and haste metastasis and suffers limited understanding of the spatial variation between primary and metastatic GC tumors. In this project, transcriptome analysis on 46 primary tumorous, adjacent non-tumorous, and metastatic GC tissues was performed. The results demonstrated that metastatic tumorous tissues had diminished CD8+ T cells compared to primary tumors, which is mechanistically attributed to being due to innate immunity differences represented by marked differences in macrophages between metastatic and primary tumors, particularly those expressing ApoE, where their abundance is linked to unfavorable prognoses. Examining variations in gene expression and interactions indicated possible strategies of immune evasion hindering the growth of CD8+ T cells in metastatic tumor tissues. More insights could be gained into the immune evasion mechanisms by portraying information about the GC ecosystem.

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Fig. 1: Single-cell RNA-seq profiling the tumor ecosystem in primary and metastatic GC.
Fig. 2: The heterogeneity of T cells in metastatic and primary tumor tissues.
Fig. 3: CD8+ T cells demonstrate different transition trajectory in primary and metastatic GC.
Fig. 4: Functional differences between metastatic and primary samples of CD8+ T cells.
Fig. 5: Forced ApoE expression in macrophages related with an immunosuppression microenvironment.
Fig. 6: ApoE is related to gastric cancer metastasis and upregulates TGF-β expression in GC.
Fig. 7: PDO model validates the suppressive effect of ApoE on T-cell function.
Fig. 8: ApoE inhibits T-cell functionality in vivo.
Fig. 9: ApoE suppresses T-cell function.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files.

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Acknowledgements

We owe our thanks to Figdraw and Biorender. Figures 1A and 9 created with Figdraw.com. Figures 7F and 8A created with BioRender.com.

Funding

We express our gratitude to the patients for their support, as well as the National Natural Science Foundation of China (81802370, 82172925, 82072575) and the Youth Foundations of Zhongshan Hospital Fudan University (2022ZSQN09, 2023ZYYS-016) for their financial assistance.

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Author notes

  1. These authors contributed equally: Yu Dong, Keshu Hu, Jiayu Zhang, Mengxuan Zhu.

Authors and Affiliations

  1. Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Yu Dong, Keshu Hu, Jiayu Zhang, Mengxuan Zhu, Mengling Liu, Yitao Yuan, Xun Sun, Zhenghang Xu, Suyao Li, Yanjing Zhu, Chi Zhang, Pengfei Zhang & Tianshu Liu

  2. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai, 20032, China

    Tianshu Liu

  3. Center of Evidence-based Medicine, Fudan University, Shanghai, China

    Tianshu Liu

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Contributions

LTS and ZPF conceived the project, designed the research, and supervised the experiments; DY acquired data together with HKS; ZJY and LML analyzed and interpreted data; YYT, SX, XZH, LSY and ZYJ collected and assembled data; ZMX revised the manuscript for important intellectual content; LTS and ZPF obtained funding and provided technical and material support.

Corresponding authors

Correspondence to Pengfei Zhang or Tianshu Liu.

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Ethics approval and consent to participate

The Ethical Review Board of Zhongshan Hospital has reviewed this study, with approval NO. B2022-540R, and patients have provided informed consent.

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Dong, Y., Hu, K., Zhang, J. et al. ScRNA-seq of gastric cancer tissues reveals differences in the immune microenvironment of primary tumors and metastases. Oncogene (2024). https://doi.org/10.1038/s41388-024-03012-5

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