Dataset Information

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

ABSTRACT: Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell suspensions of tumor and healthy adjacent tissues were analyzed for the presence of TREM2⁺ macrophages and TAMs using flow cytometry. The serum levels of soluble TREM2 (sTREM2) were quantified using an enzyme-linked immunosorbent assay. High TREM2 expression was associated with advanced UICC stages (Spearman's rank correlation (SRC), p = 0.04) and significantly reduced survival rates in primary tumors (multivariate Cox regression, progression-free survival: hazard ratio (HR) of 2.548, 95% confidence interval (CI) of 1.089-5.964, p = 0.028; overall survival: HR of 2.17, 95% CI of 1.021-4.613, p = 0.044). TREM2 expression was significantly increased in the PBMCs of OSCC patients in UICC stage IV compared with healthy controls (ANOVA, p < 0.05). The serum levels of sTREM2 were higher in advanced UICC stages, but they narrowly missed significance (SRC, p = 0.059). We demonstrated that TREM2 was multi-factorially associated with advanced stages and inferior prognosis in OSCC patients and that it could serve as a prognostic biomarker in OSCC patients. Targeting TREM2 has the potential to reshape the local and systemic immune landscape for the potential enhancement of patients' prognosis.

SUBMITTER: Struckmeier AK

PROVIDER: S-EPMC9561992 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

Struckmeier Ann-Kristin AK Radermacher Anne A Fehrenz Michael M Alansary Dalia D Wartenberg Philipp P Wagner Mathias M Scheller Anja A Hess Jochen J Moratin Julius J Freudlsperger Christian C Hoffmann Jürgen J Thurner Lorenz L Roemer Klaus K Freier Kolja K Horn Dominik D

Cancers 20220924 19

Triggering receptor expressed on myeloid cells 2 (TREM2) is suggested to hamper antitumor immune response in multiple cancers. However, the role of TREM2 in oral squamous cell carcinoma (OSCC) and its expression in tumor-associated macrophages (TAMs) are unknown. In this study, TREM2 expression was analyzed in the primary tumors and corresponding lymph-node metastases of OSCC patients via immunohistochemistry on tissue microarrays. Human peripheral blood mononuclear cells (PBMCs) and single-cell ...[more]

PMID: 36230558

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Project description:BackgroundIt 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 resultsWe 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.ConclusionOverall, 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.

Project description:Purpose: In a previous study, we found that transforming growth factor beta-induced (TGFBI) is a hub gene strongly associated with oral squamous cell carcinoma (OSCC), using gene chip meta-analysis and PPI network analysis. Thus, the present study was established to explore the role of TGFBI in the pathogenesis of OSCC and to define the underlying mechanisms. Methods: The correlations between TGFBI expression and the clinicopathological features and prognosis of OSCC were analyzed. Then, TGFBI-knockout HSC-3 cell lines were constructed using the CRISPR/Cas9 system. Cell proliferation, migration, and invasion in vitro were determined by cell counting, CCK-8, colony formation, and Transwell assays. Moreover, a xenograft animal study was implemented to determine the tumorigenicity and metastatic ability associated with TGFBI in vivo. The genes and pathways differentially expressed after TGFBI knockout were determined using transcriptional sequencing and bioinformatics. Results: TGFBI expression was significantly higher in OSCC than in normal tissue. Its high expression was also correlated with high stage and was predictive of poor prognosis, as we expected. Knockout of TGFBI inhibited cell proliferation and clone formation, and enhanced cell migration and invasion in vitro. Besides, the xenograft animal study showed that TGFBI knockout suppressed tumor growth and metastasis in vivo. Furthermore, transcriptome sequencing revealed that genes associated with cell proliferation, metastasis, and inflammatory responses exhibited a change of expression upon TGFBI knockout. GO and KEGG analyses indicated that the function of TGFBI is related to responses to bacteria and inflammatory responses. Conclusions: TGFBI overexpression can promote OSCC and is associated with poor prognosis in OSCC patients. TGFBI knockout can inhibit cell proliferation and metastasis in vivo. TGFBI may alter cell responses to bacteria, which causes an imbalance in the immune inflammatory response and promotes the development of OSCC.

Dataset Information

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

Publications

TREM2 Is Associated with Advanced Stages and Inferior Prognosis in Oral Squamous Cell Carcinoma.

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