Systematic Pan-Cancer Analysis Identifies TREM2 as an Immunological and Prognostic Biomarker

Abstract

Triggering receptor expressed on myeloid cells-2 (TREM2) is a transmembrane receptor of the immunoglobulin superfamily and a crucial signaling hub for multiple pathological pathways that mediate immunity. Although increasing evidence supports a vital role for TREM2 in tumorigenesis of some cancers, no systematic pan-cancer analysis of TREM2 is available. Thus, we aimed to explore the prognostic value, and investigate the potential immunological functions, of TREM2 across 33 cancer types. Based on datasets from The Cancer Genome Atlas, and the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal, and Human Protein Atlas, we employed an array of bioinformatics methods to explore the potential oncogenic roles of TREM2, including analyzing the relationship between TREM2 and prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA methylation, and immune cell infiltration of different tumors. The results show that TREM2 is highly expressed in most cancers, but present at low levels in lung cancer. Further, TREM2 is positively or negatively associated with prognosis in different cancers. Additionally, TREM2 expression was associated with TMB and MSI in 12 cancer types, while in 20 types of cancer, there was a correlation between TREM2 expression and DNA methylation. Six tumors, including breast invasive carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma, kidney renal clear cell carcinoma, lung squamous cell carcinoma, skin cutaneous melanoma, and stomach adenocarcinoma, were screened out for further study, which demonstrated that TREM2 gene expression was negatively correlated with infiltration levels of most immune cells, but positively correlated with infiltration levels of M1 and M2 macrophages. Moreover, correlation with TREM2 expression differed according to T cell subtype. Our study reveals that TREM2 can function as a prognostic marker in various malignant tumors because of its role in tumorigenesis and tumor immunity.

Identification of MICALL2 as a Novel Prognostic Biomarker Correlating with Inflammation and T Cell Exhaustion of Kidney Renal Clear Cell Carcinoma

“…The ssGSEA using R package "GSVA" was applied for the quantification of 11 immune signatures, including MHC class I, APC co inhibition, chemokine receptors (CCR), APC co stimulation, T cell co-inhibition, check-point, T cell co-stimulation, inflammationpromoting, parainflammation, Type I IFN response, and Type II IFN response [20]. The R packages "reshape2" and "RColorBrewer" were applied to perform a co-expression analysis of MICALL2 and immunoregulatory genes associated with major histocompatibility complex (MHC), immunosuppression, immune activation, chemokines, and chemokine receptors [21].…”

TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy

“…In addition, Xiong et al reanalyzed a publicly available scRNA-seq dataset of melanoma samples of patients subjected to ICIs and identified a subpopulation of macrophages overexpressing TREM2 that were overrepresented in the non-responding tumors, and this subpopulation of macrophages might contribute to the resistance of ICIs (89). In order to systematically explore the potential immunological functions and the potential prognostic value of TREM2 across 33 cancer types, Cheng et al conducted a pancancer analysis based on datasets from The Cancer Genome Atlas, the Cancer Cell Line Encyclopedia, Genotype Tissue-Expression, cBioPortal and Human Protein Atlas, they used the ESTIMATE algorithm to calculate the immune scores across the 33 types of cancers, their results showed that the expression level of TREM2 was significantly positively correlated with immune scores in diffuse large B-cell lymphoma, acute myeloid leukemia and thymoma, and the levels of immune cell infiltration were significantly correlated with TREM2 expression in most types of malignancies (90), this indicated that TREM2 could function as a prognostic marker in various cancers because of its especial role in tumorigenesis and tumor immunity. Lately, Lee et al demonstrated for the first time that precursor natural killer (pNK) cells expressed TREM2, compared with wild type mice, the population of pNK cells and the expression levels of NK cell-activating receptors and NK cell-associated genes were all increased in TREM2-overexpressing transgenic mice, on the contrary, the inhibition of TREM2 signaling pathway by TREM2-immunoglobulin or PI3K inhibitor impacted the expression of NK cell receptor repertoire and downregulated the expression levels of NK cell-associated genes, thus significantly impaired the differentiation of NK cells, the results of this study collectively suggested again that TREM2 might act as a novel candidate for cancer immunotherapy (91).…”

Pan-Cancer Analysis Identified C1ORF112 as a Potential Biomarker for Multiple Tumor Types

“…To widen the potential therapy options for malignancies, a better knowledge of carcinogenesis and tumor progression through the identification of oncogenes is crucial. Large-scale and multi-omics cancer datasets, such as The Cancer Genome Atlas (TCGA) ( ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium, 2020 ; Ye et al, 2021 ; Lv et al, 2021 ; Cheng et al, 2021 ; Cui et al, 2020 ), have made pan-cancer analysis possible in the last decade.…”