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MUC1-C Induces PD-L1 and Immune Evasion in Triple-Negative Breast Cancer
- Source :
- Cancer Research. 78:205-215
- Publication Year :
- 2018
- Publisher :
- American Association for Cancer Research (AACR), 2018.
-
Abstract
- The immune checkpoint ligand PD-L1 and the transmembrane mucin MUC1 are upregulated in triple-negative breast cancer (TNBC), where they contribute to its aggressive pathogenesis. Here, we report that genetic or pharmacological targeting of the oncogenic MUC1 subunit MUC1-C is sufficient to suppress PD-L1 expression in TNBC cells. Mechanistic investigations showed that MUC1-C acted to elevate PD-L1 transcription by recruitment of MYC and NF-κB p65 to the PD-L1 promoter. In an immunocompetent model of TNBC in which Eo771/MUC1-C cells were engrafted into MUC1 transgenic mice, we showed that targeting MUC1-C associated with PD-L1 suppression, increases in tumor-infiltrating CD8+ T cells and tumor cell killing. MUC1 expression in TNBCs also correlated inversely with CD8, CD69, and GZMB, and downregulation of these markers associated with decreased survival. Taken together, our findings show how MUC1 contributes to immune escape in TNBC, and they offer a rationale to target MUC1-C as a novel immunotherapeutic approach for TNBC treatment. Significance: These findings show how upregulation of the transmembrane mucin MUC1 contributes to immune escape in an aggressive form of breast cancer, with potential implications for a novel immunotherapeutic approach. Cancer Res; 78(1); 205–15. ©2017 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Mice, Transgenic
Triple Negative Breast Neoplasms
Biology
digestive system
B7-H1 Antigen
Article
Epigenesis, Genetic
GZMB
03 medical and health sciences
0302 clinical medicine
Immune system
Protein Domains
Downregulation and upregulation
Cell Line, Tumor
PD-L1
Animals
Humans
skin and connective tissue diseases
neoplasms
Triple-negative breast cancer
MUC1
Mucin-1
NF-kappa B
Xenograft Model Antitumor Assays
biological factors
digestive system diseases
Immune checkpoint
Gene Expression Regulation, Neoplastic
Protein Subunits
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
Neoplastic Stem Cells
Cancer research
biology.protein
Female
Tumor Escape
CD8
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 78
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....9eef5c7797b038ba0e6dbabc2cbe967d