Identification of TREM2-positive tumor-associated macrophages in esophageal squamous cell carcinoma: implication for poor prognosis and immunotherapy modulation.

Abstract

Background:

It is now understood that the effectiveness of checkpoint immunotherapy can be impaired by immunosuppressive tumor-associated macrophages (TAMs). Nonetheless, the impact of different TAM subpopulations on the antitumor immune response remains unclear, mainly due to their heterogeneity. Herein, we identified a novel TAM subpopulation in esophageal squamous cell carcinoma (ESCC) that might contribute to poor clinical outcomes and immunotherapy modulation.

Methods and results:

We analyzed two single-cell RNA sequencing (scRNA-seq) datasets (GSE145370 and GSE160269) of esophageal squamous cell carcinoma to identify a novel TREM2-positive TAM subpopulation characterized by upregulation of TREM2, C1QC, C1QB, C1QA, SPP1, and APOE. Quantitative real-time PCR (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) demonstrated that these genes were significantly overexpressed in ESCC. Multiplex immunofluorescence validated the infiltration of TREM2+ TAMs in ESCC tissues, which correlated with poorer overall survival (OS). The scRNA-seq analysis in dataset GSE120575 indicated significant enrichment of TREM2+ TAMs in melanoma patients (n=48) with poor immunotherapy response, which had an identical gene signature with TREM2+ TAMs from ESCC. Analysis of 29 bulk-RNA melanoma samples from dataset GSE78220 revealed that a gene signature of 40 genes associated with TREM2+ TAMs was upregulated in the transcriptome of melanomas that did not respond to anti-PD1 therapy. Validation in the TCGA ESCC cohort (n=80) showed that a high enrichment score of the TREM2+ TAM was associated with poor prognosis. In addition, 10 ESCC patients treated with anti-PD1 therapy suggested that patients who are not sensitive to immunotherapy have higher density of TREM2+TAMs infiltration.

Conclusion:

Overall, TREM2+ TAM infiltration in ESCC is associated with poor prognosis and may serve as a biomarker for predicting outcomes and immunotherapy modulation in this patient population. modulation; single-cell RNA sequencing.

• Authors: Hongmu Li, Yu Miao, Leqi Zhong, Songjie Feng, Yue Xu, Lu Tang, Chun Wu, Xianzhou Zhang, Ling Gu, Hengyi Diao, Huiyun Wang, Zhesheng Wen, Minglei Yang
• Journal: Frontiers in immunology (Front Immunol) Vol. 14 Pg. 1162032 ( 2023) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 37187751 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Li, Miao, Zhong, Feng, Xu, Tang, Wu, Zhang, Gu, Diao, Wang, Wen and Yang.

Chemical References

• TREM2 protein, human
• Membrane Glycoproteins
• Receptors, Immunologic

Topics

• Humans
• Esophageal Squamous Cell Carcinoma (therapy, drug therapy)
• Esophageal Neoplasms (genetics, therapy)
• Tumor-Associated Macrophages (pathology)
• Cell Line, Tumor
• Immunotherapy
• Prognosis
• Membrane Glycoproteins (genetics)
• Receptors, Immunologic (genetics, therapeutic use)