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Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer

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Abstract

Background

Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME.

Methods

Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients.

Results

The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues. The M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues. Among the immunosuppressive cell types assessed, the M-MDSCs were most enriched in GC tissues relative to adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P = 0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3− M-MDSCs and were abundant in treatment-resistant GC patients.

Conclusions

The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.

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Data availability and materials

The scRNA-seq data generated in this study are available from the GEO database under accession code GSE231540. The remaining data are available within the manuscript, Supplementary Information, or from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to E. Manabe and S. Sadatomi (Kyushu University) for their expert technical assistance. We also thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

K. Ohuchida has received grants from JSPS KAKENHI (grant numbers JP20K17621, JP21K08800, JP21K07244, JP22H00480 and JP23H02770). C. Tsutsumi has received grants from JSPS Research Fellow DC2 (23KJ1698) and Support for Pioneering Research Initiated by the Next Generation (SPRING) “Future-Creation (MIRAI)” Course (JPMJSP2136). The other authors have nothing to disclose.

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Authors and Affiliations

  1. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Chikanori Tsutsumi, Kenoki Ohuchida, Naoki Katayama, Shoichi Nakamura, Sho Okuda, Yoshiki Otsubo, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Eishi Nagai & Masafumi Nakamura

  2. Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Kenoki Ohuchida

  3. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Yutaka Yamada & Yoshinao Oda

  4. Department of Cancer Immunotherapy, Fukuoka General Cancer Clinic, Fukuoka, Japan

    Takashi Morisaki

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  1. Chikanori Tsutsumi
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  2. Kenoki Ohuchida
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Contributions

CT designed and performed the experiments, analyzed the data, coordinated the research, and wrote the manuscript. KO designed the experiments, analyzed the data, wrote the manuscript, coordinated the research, and contributed to data interpretation and discussion. NK, YO, SN, and KO performed the experiments. CI, YM, NI, KN, EN, and TM contributed to data interpretation and discussion. KO, NT, KH, and KS obtained and prepared human samples. Immunohistochemically stained samples were analyzed by CT, YY, and YO. MN coordinated the research, wrote the manuscript, and contributed to data interpretation and discussion.

Corresponding author

Correspondence to Kenoki Ohuchida.

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Conflict of interest

The authors have no conflicts of interest.

Ethical approval and consent to participate

Clinical data, including histopathological findings, were obtained from the patients’ electronic medical records. Written informed consent was obtained from all participating patients and the study was approved by the Ethics Committee of Kyushu University (approval number: 22002-00 and 2020-7882020-503) and conducted in accordance with the Ethical Guidelines for Human Genome/Gene Research enacted by the Japanese Government and the Declaration of Helsinki.

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Tsutsumi, C., Ohuchida, K., Katayama, N. et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer. Gastric Cancer 27, 248–262 (2024). https://doi.org/10.1007/s10120-023-01456-4

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