MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer

A. Bouillez, H. Rajabi, C. Jin, M. Samur, A. Tagde, M. Alam, M. Hiraki, T. Maeda, X. Hu, D. Adeegbe, S. Kharbanda, K. K. Wong, D. Kufe

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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.

Original languageEnglish
Pages (from-to)4037-4046
Number of pages10
JournalOncogene
Volume36
Issue number28
DOIs
Publication statusPublished - Jul 13 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Bouillez, A., Rajabi, H., Jin, C., Samur, M., Tagde, A., Alam, M., Hiraki, M., Maeda, T., Hu, X., Adeegbe, D., Kharbanda, S., Wong, K. K., & Kufe, D. (2017). MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. Oncogene, 36(28), 4037-4046. https://doi.org/10.1038/onc.2017.47