Journal
FRONTIERS IN ONCOLOGY
Volume 11, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2021.734959
Keywords
TREM-1; tumor infiltrating myeloid cells; transcriptomics; immune signature; cytokines; breast cancer; immune suppression
Categories
Funding
- American Cancer Society [RSG-12-198-01-TBG]
- Mary Kirkpatrick Professorship for Breast Cancer Research
- NIH [T32-CA079448]
- Wake Forest Baptist Compressive Cancer Center's Cancer Genomics Shared Resource (CGSR)
- Bioinformatics Shared Resource (BISR)
- Tumor Tissue and Pathology Shared Resource (TTPSR) - National Cancer Institute's Cancer Center Support Grant [P30CA012197]
- Indiana University Precision Health Initiative
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High TREM-1 expression is associated with poor prognosis in breast cancer, potentially contributing to tumor progression and immune suppression through myeloid cells.
BackgroundTriggering receptor expressed on myeloid cells (TREM)-1 is a key mediator of innate immunity previously associated with the severity of inflammatory disorders, and more recently, the inferior survival of lung and liver cancer patients. Here, we investigated the prognostic impact and immunological correlates of TREM1 expression in breast tumors. MethodsBreast tumor microarray and RNAseq expression profiles (n=4,364 tumors) were analyzed for associations between gene expression, tumor immune subtypes, distant metastasis-free survival (DMFS) and clinical response to neoadjuvant chemotherapy (NAC). Single-cell (sc)RNAseq was performed using the 10X Genomics platform. Statistical associations were assessed by logistic regression, Cox regression, Kaplan-Meier analysis, Spearman correlation, Student's t-test and Chi-square test. ResultsIn pre-treatment biopsies, TREM1 and known TREM-1 inducible cytokines (IL1B, IL8) were discovered by a statistical ranking procedure as top genes for which high expression was associated with reduced response to NAC, but only in the context of immunologically hot tumors otherwise associated with a high NAC response rate. In surgical specimens, TREM1 expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High TREM1 significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high TREM1 and inferior DMFS was most prominent in the subset of immunogenic tumors that exhibited the immunologically hot phenotype and otherwise associated with superior DMFS. Further observations from bulk and single-cell RNAseq analyses indicated that TREM1 expression was significantly enriched in polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and M2-like macrophages, and correlated with downstream transcriptional targets of TREM-1 (IL8, IL-1B, IL6, MCP-1, SPP1, IL1RN, INHBA) which have been previously associated with pro-tumorigenic and immunosuppressive functions. ConclusionsTogether, these findings indicate that increased TREM1 expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.
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