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Published on: November 28, 2019
SIGLEC10+ macrophages drive gastric cancer progression by suppressing CD8+ T cell function
Yixian Guo1, Shouyu Ke2, Feng Xie3,4
1GI Division, School of Medicine, Renji Hospital, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200025, China.
Abstract:
Existing immune checkpoint inhibitors focus on activating T cells and show limited effectiveness in gastric cancer (GC). SIGLEC10 is identified as a novel tumor-associated macrophage-related immune checkpoint in other cancer types. However, its immunosuppressive role and clinical significance in GC remain unclear. In this study, we find a dominant expression of SIGLEC10 on CD68+ macrophages in GC. SIGLEC10 can suppress the proliferation and function of tumor-infiltrating CD8+ T cells in vitro via the Akt/P38/Erk signaling pathway. Furthermore, in ex vivo and in vivo models, SIGLEC10 blockade promotes CD8+ T cell effector function. Finally, SIGLEC10+ macrophages are positively correlated with the adverse prognosis of GC. Our study highlights that SIGLEC10 directly suppresses T cell function and serves as a promising target for immunotherapy and suggests SIGLEC10+ macrophages as a novel potential predictor of the clinical prognosis of GC.
Insights
SIGLEC10 on macrophages suppresses T cell function in gastric cancer. Blocking SIGLEC10 may enhance immunotherapy and predict patient prognosis.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Current T cell-focused immune checkpoint inhibitors have limited efficacy in gastric cancer (GC).
- SIGLEC10, a macrophage immune checkpoint, has an unclear role in GC.
- Tumor-associated macrophages (TAMs) are key players in the GC tumor microenvironment.
Purpose of the Study:
- To investigate the role of SIGLEC10 in gastric cancer immunity.
- To determine if SIGLEC10 is a potential therapeutic target for GC immunotherapy.
- To assess the prognostic value of SIGLEC10+ macrophages in GC.
Main Methods:
- Analysis of SIGLEC10 expression on CD68+ macrophages in GC tissues.
- In vitro experiments assessing SIGLEC10's effect on CD8+ T cell proliferation and function.
- In vitro and in vivo studies evaluating the impact of SIGLEC10 blockade.
- Correlation analysis between SIGLEC10+ macrophages and GC patient prognosis.
Main Results:
- SIGLEC10 is predominantly expressed on CD68+ macrophages in GC.
- SIGLEC10 suppresses CD8+ T cell proliferation and function via the Akt/P38/Erk pathway.
- SIGLEC10 blockade enhances CD8+ T cell effector functions in ex vivo and in vivo models.
- High SIGLEC10+ macrophage infiltration correlates with adverse GC prognosis.
Conclusions:
- SIGLEC10 directly inhibits T cell function in the gastric cancer microenvironment.
- SIGLEC10 represents a promising novel target for GC immunotherapy.
- SIGLEC10+ macrophages may serve as a predictive biomarker for GC clinical outcomes.
