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FGL1 facilitates rather than suppresses anticancer immunity against microsatellite instable gastric cancer

Genes & Immunity volume 26, pages 36–44 (2025)Cite this article

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Abstract

Microsatellite instability (MSI) is a phenotype characterized by changes in the sequence length of microsatellites in tumor cells and is closely linked to tumorigenesis and prognosis. Immune checkpoint inhibitors have shown good therapeutic effects in gastric cancer (GC) with MSI-high (MSI-H). However, the role of the novel immune checkpoint fibrinogen-like protein 1 (FGL1) in GC treatment has not been fully investigated. FGL1 expression in GC tissues and the difference in FGL1 immune infiltration between MSI/ microsatellite stability (MSS) patients were analyzed by bioinformatics and were verified in clinical samples. Xenograft models of MSS and MSI GC were constructed in human immune reconstitution mice, and FGL1 expression in tumors was detected. Immunofluorescence and immunohistochemistry were used to assay the infiltration of immune cells in the two types of mice. Cytotoxicity and chemotaxis tests were used to detect the toxicity and chemotaxis of CD8+T cells to GC cells, respectively. The cytokine content was detected by enzyme-linked immunosorbent assay. The therapeutic effects of FGL1 antibody on different types of GC were analyzed by xenograft mouse models. FGL1 exhibited significantly higher expression in GC, and its expression and immune cell infiltration levels were significantly higher in MSI GC than in MSS GC. CD8+T cells were significantly more effective in killing and chemotaxis of MSI GC cells than MSS GC cells. The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.

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Fig. 1: FGL1 is highly expressed in MSI GC.
Fig. 2: MSI GC has a higher level of immune cell infiltration.
Fig. 3: FGL1 antibody inhibits immune escape in MSI GC.
Fig. 4: MSI GC mice are more sensitive to anti-FGL1 treatment.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

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Funding

This research was supported by Natural Science Foundation of Zhejiang Province under grant number LY21H160053 and Hangzhou Medical College basic research key project under grant number KYZD2023011.

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Authors and Affiliations

  1. General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China

    Zhenyuan Qian, Jianzhang Wu, Kun Ke, Zaiyuan Ye & Fang Wu

  2. Zhejiang Chinese Medicine University, Hangzhou, Zhejiang, China

    Xufan Cai

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  1. Zhenyuan Qian
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  2. Xufan Cai
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  3. Jianzhang Wu
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  4. Kun Ke
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Contributions

ZYQ conceived and designed the study. XFC, JZW, and KK performed the experiments and collected the data. ZYY analyzed and interpreted the data. FW contributed to the manuscript writing and editing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zaiyuan Ye or Fang Wu.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the Zhejiang Provincial People’s Hospital, Affiliated People’s Hospital Ethics Committee with approval number 202403251133000525844. And obtained informed consent from the patient. All animals were kept in a pathogen-free environment and fed ad lib. The procedures for care and use of animals were approved by the Ethics Committee of Zhejiang Provincial People’s Hospital with approval number 20230419162308960584 and all applicable institutional and governmental regulations concerning the ethical use of animals were followed. All methods were performed in accordance with the relevant guidelines and regulations.

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Qian, Z., Cai, X., Wu, J. et al. FGL1 facilitates rather than suppresses anticancer immunity against microsatellite instable gastric cancer. Genes Immun 26, 36–44 (2025). https://doi.org/10.1038/s41435-024-00314-2

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