https://orcid.org/0000-0001-6200-9885
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Abstract
Background
Triggering receptors expressed by myeloid cells-1 (TREM1) is a receptor belonging to the immunoglobulin superfamily and plays an important role in pro-inflammation in acute and chronic inflammatory disorders. However, the understanding of the immunomodulatory roles of TREM1 in the tumor microenvironment remains incomplete.
Methods
The expression patterns of TREM1 mRNA in tumors and adjacent normal tissues were compared by analyzing data obtained from the Genotype-Tissue Expression and The Cancer Genome Atlas datasets. Survival analysis was performed to determine the prognostic value of TREM1. Functional enrichment analysis was applied to decipher the discrepancy in biological processes between high- and low-TREM1 groups across various cancers. The correlation between TREM1 and immune cell infiltration determined by using multiple algorithms was evaluated with the Pearson method. Four independent immunotherapy cohorts were adopted to validate the role of TREM1 as a biomarker.
Results
TREM1 was elevated in most cancers as verified with clinical samples. Overexpression of TREM1 was linked with undesirable prognosis in patients. Further analysis revealed that TREM1 was positively correlated with immune response, pro-tumor pathways, and myeloid cell infiltration, while being negatively correlated with CD8+ T cell (including infiltration level and biological processes). Concordantly, tumors with high TREM1 levels were more resistant to immunotherapy. Through connective map analysis, therapeutically potential compounds like tozasertib and TPCA-1 were identified, which can be used synergistically with immunotherapy to improve the poor prognosis of patients with high TREM1 levels.
Conclusion
Through a systematic and comprehensive pan-cancer analysis, we demonstrated that overexpression of TREM1 in tumors correlated closely with unfavorable outcome, infiltration of immune-suppressive cells, and immune regulation, which highlights its potential use as a tumor prognostic biomarker and a novel target for immunotherapy.
Abbreviation
AJCC, American Joint Committee on Cancer; CAFs, cancer-associated fibroblasts; CMap, The Connectivity Map; DCs, dendritic cells; DSS, disease-specific survival; DEGs, differentially expressed genes; EMT, epithelial–mesenchymal transition; GO, Gene Ontology; GSEA, Gene Set Enrichment Analysis; GTEx, Genotype-tissue expression; IC50, semi-inhibitory concentration; ICI, immune checkpoint inhibitor; IHC, immunohistochemistry; KEGG, Kyoto Encyclopedia of Genes and Genomes; K-M, Kaplan-Meier; MDSCs, myeloid-derived suppressor cells; MSI, microsatellite instability; mUC, metastatic urothelial cancer; MultiCox, multivariate Cox regression; NEO, tumor neoantigen; OS, overall survival; qRT-PCR, quantitative real-time PCR; RCC, renal cell carcinoma; ssGSEA, single-sample gene set enrichment analysis; TCGA, The Cancer Genome Atlas; TMB, tumor mutation burden; TME, tumor microenvironment; TPM, transcripts per million; Tregs, T-regulatory lymphocytes; TREM1, triggering receptors expressed by myeloid cells-1; UniCox, univariate Cox regression; UALCAN, The University of Alabama at Birmingham Cancer data analysis Portal. Abbreviation list of cancers in TCGA are in Table S1.
Data Sharing Statement
The datasets supporting the conclusions of this article are available in the UCSC Xena (https://xenabrowser.net/datapages/), cBioPortal (www.cbioportal.org), TIMER2.0 (http://timer.cistrome.org/), and published research, which have been described in Method.
Ethics Statement
The studies involving human participants were reviewed and approved by Institutional Ethics Committee for Clinical Research and Animal Trials Ethical of the First Affiliated Hospital of Sun Yat-sen University [(2021)143], [(2021)144]. The patients/participants provided their written informed consent to participate in this study.
Consent for Publication
Written informed consent for publication was obtained from all participants.
Acknowledgment
We would like to express our sincere appreciation to UCSC Xena, UALCAN, TIMER2.0, cBioPortal, and CMap for providing the data used in this study.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; XZ and KL took part in drafting, revising the article, which was critically reviewed and edited by JC and PL; all authors gave final approval of the version to be published and agreed on the journal to which the article has been submitted; all authors agreed to be accountable for all aspects of the work.
Disclosure
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.