AUTHOR=Pullikuth Ashok K. , Routh Eric D. , Zimmerman Kip D. , Chifman Julia , Chou Jeff W. , Soike Michael H. , Jin Guangxu , Su Jing , Song Qianqian , Black Michael A. , Print Cristin , Bedognetti Davide , Howard-McNatt Marissa , O’Neill Stacey S. , Thomas Alexandra , Langefeld Carl D. , Sigalov Alexander B. , Lu Yong , Miller Lance D. 

TITLE=Bulk and Single-Cell Profiling of Breast Tumors Identifies TREM-1 as a Dominant Immune Suppressive Marker Associated With Poor Outcomes

JOURNAL=Frontiers in Oncology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2021.734959

DOI=10.3389/fonc.2021.734959

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>Triggering 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 <italic>TREM1</italic> expression in breast tumors.</p></sec><sec><title>Methods</title><p>Breast 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.</p></sec><sec><title>Results</title><p>In pre-treatment biopsies, <italic>TREM1</italic> 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, <italic>TREM1</italic> expression varied among tumor molecular subtypes, with highest expression in the more aggressive subtypes (Basal-like, HER2-E). High <italic>TREM1</italic> significantly and reproducibly associated with inferior distant metastasis-free survival (DMFS), independent of conventional prognostic markers. Notably, the association between high <italic>TREM1</italic> 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 <italic>TREM1</italic> 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 (<italic>IL8</italic>, <italic>IL-1B</italic>, <italic>IL6</italic>, <italic>MCP-</italic>1, <italic>SPP1, IL1RN, INHBA</italic>) which have been previously associated with pro-tumorigenic and immunosuppressive functions.</p></sec><sec><title>Conclusions</title><p>Together, these findings indicate that increased <italic>TREM1</italic> expression is prognostic of inferior breast cancer outcomes and may contribute to myeloid-mediated breast cancer progression and immune suppression.</p></sec>