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TREM1 Blockade Reprograms Tumor-Associated Macrophages and Improves Anti-PD-1 Efficacy in Gastric Cancer
Jinnan Chen1, Tianwei Xu1, Chao Lin2
1Department of Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Objective:
The objective response rate of immune checkpoint inhibitors in patients with gastric cancer is limited. Targeting specific subtypes of macrophages holds promise for expanding the potential population sensitive to immune checkpoint inhibitors. This study aims to evaluate the key role of TREM1+tumor-associated macrophages (TAMs) in regulating antitumor immunity.
Methods And Analysis:
This study included four cohorts, consisting of three tumor microarrays and transcriptomic data from the Cancer Genome Atlas (TCGA). The association between TREM1+TAMs and clinical outcomes and genomic characteristics was analyzed. Freshly resected tumor tissues were cultured in vitro to assess the potential therapeutic effect of blockade of TREM1 in gastric cancer.
Results:
High TREM1+TAMs level indicates poor prognosis and tumor progression in patients with resectable gastric cancer. TREM1+TAMs infiltration is negatively associated with objective response rate to immune checkpoint inhibitors in patients with advanced gastric cancer. TREM1+TAMs lead to dysfunction of CD8+T cells by expressing PD-L1 and TGFβ. Finally, we show that inhibiting TREM1+TAMs promotes antitumor immunity in gastric cancer.
Conclusions:
TREM1+TAMs infiltration was an independent prognostic predictor in patients with gastric cancer. TREM1+TAMs contributed to the immune escape by displaying PD-L1 and TGFβ. Blockade of TREM1 drove antitumor response, providing potential therapeutic effects for gastric cancer patients.
Insights
High levels of TREM1-positive tumor-associated macrophages (TAMs) predict poor outcomes in gastric cancer. Blocking TREM1+ TAMs enhances antitumor immunity, offering a potential therapeutic strategy for gastric cancer patients.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Immune checkpoint inhibitors (ICIs) show limited efficacy in gastric cancer.
- Targeting specific macrophage subtypes may enhance ICI sensitivity.
- Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment.
Purpose of the Study:
- To investigate the role of TREM1-positive TAMs (TREM1+ TAMs) in gastric cancer immunity.
- To evaluate TREM1+ TAMs as a prognostic biomarker.
- To assess the therapeutic potential of blocking TREM1 in gastric cancer.
Main Methods:
- Analysis of tumor microarrays and TCGA transcriptomic data from four cohorts.
- Correlation analysis of TREM1+ TAMs with clinical outcomes and genomic features.
- In vitro culture of gastric cancer tissues to test TREM1 blockade.
Main Results:
- High TREM1+ TAMs levels correlate with poor prognosis and tumor progression.
- TREM1+ TAMs infiltration is linked to lower response rates to ICIs.
- TREM1+ TAMs impair CD8+ T cell function via PD-L1 and TGFβ expression.
- Inhibition of TREM1+ TAMs enhances antitumor immunity.
Conclusions:
- TREM1+ TAMs are an independent prognostic marker for gastric cancer.
- TREM1+ TAMs promote immune escape through PD-L1 and TGFβ.
- Blocking TREM1 demonstrates therapeutic potential against gastric cancer by promoting antitumor response.
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