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

• Published in: Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association Vol. 27; no. 2; pp. 248 - 262
• Main Authors: Tsutsumi, Chikanori, Ohuchida, Kenoki, Katayama, Naoki, Yamada, Yutaka, Nakamura, Shoichi, Okuda, Sho, Otsubo, Yoshiki, Iwamoto, Chika, Torata, Nobuhiro, Horioka, Kohei, Shindo, Koji, Mizuuchi, Yusuke, Ikenaga, Naoki, Nakata, Kohei, Nagai, Eishi, Morisaki, Takashi, Oda, Yoshinao, Nakamura, Masafumi
• Format: Journal Article
• Language: English
• Published: Singapore Springer Nature Singapore 01-03-2024; Springer Nature B.V
• Subjects: Abdominal Surgery; Cancer Research; Gastric cancer; Gastroenterology; Gene Expression; Humans; Immune checkpoint inhibitors; Immunosuppression; Medicine; Medicine & Public Health; Monocytes; Myeloid-Derived Suppressor Cells - metabolism; Myeloid-Derived Suppressor Cells - pathology; Oncology; Original Article; Prognosis; Stomach Neoplasms - pathology; Suppressor cells; Surgical Oncology; Tumor Microenvironment; Immediate early response 3; Tumor immune microenvironment; Gastric cancer; Monocytic myeloid-derived suppressor cells
• ISSN: 1436-3291; 1436-3305
• DOI: 10.1007/s10120-023-01456-4

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
g
ene 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.