Abstract
Immunotherapeutic approaches, particularly programmed death 1/programmed death ligand 1 (PD-1/PD-L1) blockade, have improved the treatment of non-small-cell lung cancer (NSCLC), supporting the premise that evasion of immune destruction is of importance for NSCLC progression. However, the signals responsible for upregulation of PD-L1 in NSCLC cells and whether they are integrated with the regulation of other immune-related genes are not known. Mucin 1 (MUC1) is aberrantly overexpressed in NSCLC, activates the nuclear factor-κB (NF-κB) p65→ZEB1 pathway and confers a poor prognosis. The present studies demonstrate that MUC1-C activates PD-L1 expression in NSCLC cells. We show that MUC1-C increases NF-κB p65 occupancy on the CD274/PD-L1 promoter and thereby drives CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of NF-κB→ZEB1 signaling represses the TLR9 (toll-like receptor 9), IFNG, MCP-1 (monocyte chemoattractant protein-1) and GM-CSF genes, and that this signature is associated with decreases in overall survival. In concert with these results, targeting MUC1-C in NSCLC tumors suppresses PD-L1 and induces these effectors of innate and adaptive immunity. These findings support a previously unrecognized central role for MUC1-C in integrating PD-L1 activation with suppression of immune effectors and poor clinical outcome.
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Accession codes
Abbreviations
- NSCLC:
-
non-small cell lung cancer
- EGFR:
-
epidermal growth factor receptor
- PD-1:
-
programmed death 1
- PD-L1:
-
programmed death ligand 1
- MUC1:
-
mucin 1
- MUC1-C:
-
MUC1 C-terminal subunit
- CD274 :
-
gene encoding PD-L1
- GEMMs:
-
genetically engineered mouse models
- DOX:
-
doxycycline
- ChIP:
-
chromatin immunoprecipitation
- TLR7:
-
toll-like receptor 7
- TLR9:
-
toll-like receptor 9
- IFN-γ:
-
interferon-gamma
- MCP-1:
-
monocyte chemoattractant protein-1
- GM-CSF:
-
granulocyte-monocyte colony-stimulating factor.
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Acknowledgements
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under award numbers CA97098 and CA166480, and by the Lung Cancer Research Foundation.
Author contributions
AB, HR, K-KW, SK and DK designed the research; AB, HR, CJ, MA, MH, TM, XH and DA performed the research and data analysis; MS and AT performed bioinformatics analysis; AB, K-KW and DK wrote the manuscript.
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DK holds equity in Genus Oncology and is a consultant to the company. The authors declare no conflict of interest.
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Bouillez, A., Rajabi, H., Jin, C. et al. MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene 36, 4037–4046 (2017). https://doi.org/10.1038/onc.2017.47
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DOI: https://doi.org/10.1038/onc.2017.47
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