MUC1-C integrates activation of the IFN-γ pathway with suppression of the tumor immune microenvironment in triple-negative breast cancer

• DOI: 10.1136/jitc-2020-002115
• Publication Date: 2021-01-25T15:43:12Z
• Authors: Nami Yamashita; Mark Long; Atsushi Fushimi; Masaaki Yamamoto; Tsuyoshi Hata; Masayuki Hagiwara; Atrayee Bhattacharya; Qiang Hu; Kwok-Kin Wong; Song Liu; Donald Kufe
• Keywords: MUC1; Triple-negative breast cancer; Immune checkpoint; Tumor-infiltrating lymphocytes

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 TNBCs to ICIs is lack functional tumor-infiltrating lymphocytes (TILs) in ‘non-inflamed’ or ‘cold’ tumor immune microenvironments (TIMEs), although by unknown mechanisms. Targeting MUC1-C mouse transgenic TNBC model increases cytotoxic CD8+ T cells (CTLs), supporting role for evasion. The basis these findings and whether they extend human are not known. Methods Human silenced using short hairpin RNAs (shRNAs) were analyzed effects global transcriptional profiles. Differential expression rank order analysis was used gene set enrichment (GSEA). Gene confirmed quantitative reverse-transcription PCR immunoblotting. Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) Molecular Taxonomy International Consortium (METABRIC) datasets MUC1 GSEA, cell-type enrichment, dysfunction exclusion. Single-cell scRNA-seq samples normalized associations between selected genes within cells. Results Our results demonstrate that master regulator transcriptome MUC1-C-induced driven STAT1 IRF1. We found activates inflammatory interferon (IFN)-γ-driven JAK1→STAT1→IRF1 pathway induces IDO1 COX2/PTGS2 effectors, which play key roles immunosuppression. Involvement activating immunosuppressive IFN-γ extended bulk datasets. further associates with depletion TIME. Conclusions These integrates activation TILs TIME provide support as potential target improving alone combination ICIs. Of translational significance, druggable chimeric antigen receptor (CAR) cells, antibody-drug conjugates (ADCs) inhibitor under clinical development.