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Molecular Diagnostics

Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer

British Journal of Cancer volume 130, pages 671–681 (2024)Cite this article

Subjects

Abstract

Background

Recent studies have identified that low levels of some tumour suppressor microRNAs (miRNAs) in the blood contribute to tumour progression and poor outcomes in various cancers. However, no study has proved these miRNAs are associated with cancer immune mechanisms.

Methods

From a systematic review of the NCBI and miRNA databases, four tumour suppressor miRNA candidates were selected (miR-5193, miR-4443, miR-520h, miR-496) that putatively target programmed cell death ligand 1 (PD-L1).

Results

Test-scale and large-scale analyses revealed that plasma levels of miR-5193 were significantly lower in gastric cancer (GC) patients than in healthy volunteers (HVs). Low plasma levels of miR-5193 were associated with advanced pathological stages and were an independent prognostic factor. Overexpression of miR-5193 in GC cells suppressed PD-L1 on the surface of GC cells, even with IFN-γ stimulation. In the coculture model of GC cells and T cells stimulated by anti-CD3/anti-CD28 beads, overexpression of miR-5193 increased anti-tumour activity of T cells by suppressing PD-L1 expression. Subcutaneous injection of miR-5193 also significantly enhanced the tumour-killing activity and trafficking of T cells in mice.

Conclusions

Low blood levels of miR-5193 are associated with GC progression and poor outcomes and could be a target of nucleic acid immunotherapy in GC patients.

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Fig. 1: Investigation of miR-5193 plasma levels in GC patients.
Fig. 2: Investigation of the improvement of the anti-tumour activity of T cells in GC cells by suppressing PD-L1 expression.
Fig. 3: Overexpression of miR-5193 increased the anti-tumour activity of T cells in vivo.
Fig. 4: Evaluation of PD-L1 expression and the trafficking of T cells by the immunohistochemistry of xenografts.

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Data availability

The datasets generated and/or analysed during the current study are not publicly available due to the personal information protection law in Japan but are available after the permission from the institutional review board and the corresponding author upon reasonable request.

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Funding

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Author notes

  1. These authors contributed equally: Hajime Kamiya and Shuhei Komatsu.

Authors and Affiliations

  1. Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kawaramachi-hirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan

    Hajime Kamiya, Shuhei Komatsu, Yusuke Takashima, Ryo Ishida, Hiroshi Arakawa, Keiji Nishibeppu, Jun Kiuchi, Taisuke Imamura, Takuma Ohashi, Hiroki Shimizu, Tomohiro Arita, Hirotaka Konishi, Atsushi Shiozaki, Takeshi Kubota, Hitoshi Fujiwara & Eigo Otsuji

  2. Department of Pediatrics, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

    Shigeki Yagyu & Tomoko Iehara

  3. Center for Advanced Research of Gene and Cell Therapy in Shinshu University (CARS), Shinshu University School of Medicine, Matsumoto, Japan

    Shigeki Yagyu

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Contributions

HK and SK designed, and SK and EO reviewed the research; HK, YT, TO, JK, HA and RI performed cell cultures, molecular biology and animal experiments; SK, TA, HS, HK, AS, TK, HF, SY, TI and EO provided clinical specimens and performed clinical data analyses. All authors read and approved the final manuscript.

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Correspondence to Shuhei Komatsu.

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The authors declare no competing interests.

Ethics approval and consent to participate

All experimental methods were carried out in accordance with relevant guidelines and regulations, such as the Declaration of Helsinki. Written informed consent was obtained from all patients to use their tissue specimens and blood samples. This study was approved by the institutional review boards of Kyoto Prefectural University of Medicine (ERB-C-319-1). The animal protocol was approved by the Institutional Animal Care and Use Committee of Kyoto Prefectural University of Medicine, and all experiments were conducted strictly in accordance with the National Institute of Health Guide for Care and Use of Laboratory Animals.

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Kamiya, H., Komatsu, S., Takashima, Y. et al. Low blood level of tumour suppressor miR-5193 as a target of immunotherapy to PD-L1 in gastric cancer. Br J Cancer 130, 671–681 (2024). https://doi.org/10.1038/s41416-023-02532-3

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