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Tumor-infiltrating Monocytic Myeloid-Derived Suppressor Cells Contribute to the Development of an Immunosuppressive Tumor Microenvironment in Gastric Cancer.

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

Gastric cancer(2024)

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Abstract
BackgroundGastric 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.MethodsSingle-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.ResultsThe 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.ConclusionsThe 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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Key words
Gastric cancer,Monocytic myeloid-derived suppressor cells,Immediate early response 3,Tumor immune microenvironment
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