TY - JOUR T1 - MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer JF - Journal for ImmunoTherapy of Cancer JO - J Immunother Cancer DO - 10.1136/jitc-2020-002115 VL - 9 IS - 1 SP - e002115 AU - Nami Yamashita AU - Mark Long AU - Atsushi Fushimi AU - Masaaki Yamamoto AU - Tsuyoshi Hata AU - Masayuki Hagiwara AU - Atrayee Bhattacharya AU - Qiang Hu AU - Kwok-Kin Wong AU - Song Liu AU - Donald Kufe Y1 - 2021/01/01 UR - http://jitc.bmj.com/content/9/1/e002115.abstract N2 - Background Immune checkpoint inhibitors (ICIs) have had a profound impact on the treatment of many tumors; however, their effectiveness against triple-negative breast cancers (TNBCs) has been limited. One factor limiting responsiveness of TNBCs to ICIs is a lack of functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C in a mouse transgenic TNBC tumor model increases cytotoxic tumor-infiltrating CD8+ T cells (CTLs), supporting a role for MUC1-C in immune evasion. The basis for these findings and whether they extend to human TNBCs are not known.Methods Human TNBC cells silenced for MUC1-C using short hairpin RNAs (shRNAs) were analyzed for the effects of MUC1-C on global transcriptional profiles. Differential expression and rank order analysis was used for gene set enrichment analysis (GSEA). Gene expression was confirmed by quantitative reverse-transcription PCR and immunoblotting. The The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) datasets were analyzed for effects of MUC1 on GSEA, cell-type enrichment, and tumor immune dysfunction and exclusion. Single-cell scRNA-seq datasets of TNBC samples were analyzed for normalized expression associations between MUC1 and selected genes within tumor cells.Results Our results demonstrate that MUC1-C is a master regulator of the TNBC transcriptome and that MUC1-C-induced gene expression is driven by STAT1 and IRF1. We found that MUC1-C activates the inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway and induces the IDO1 and COX2/PTGS2 effectors, which play key roles in immunosuppression. Involvement of MUC1-C in activating the immunosuppressive IFN-γ pathway was extended by analysis of human bulk and scRNA-seq datasets. We further demonstrate that MUC1 associates with the depletion and dysfunction of CD8+ T cells in the TNBC TIME.Conclusions These findings demonstrate that MUC1-C integrates activation of the immunosuppressive IFN-γ pathway with depletion of TILs in the TNBC TIME and provide support for MUC1-C as a potential target for improving TNBC treatment alone and in combination with ICIs. Of translational significance, MUC1-C is a druggable target with chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs) and a functional inhibitor that are under clinical development.Data are available in a public, open access repository. The accession number for the RNA-seq data reported in this paper is GEO ACCESSION GSE164141. ER -