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

Oncogene. 2017 Jul 13;36(28):4037-4046. doi: 10.1038/onc.2017.47. Epub 2017 Mar 13.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Animals
  • B7-H1 Antigen / genetics*
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Carcinoma, Non-Small-Cell Lung* / immunology
  • Carcinoma, Non-Small-Cell Lung* / pathology
  • Cell Line, Tumor
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunity, Cellular / genetics*
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / immunology
  • Lung Neoplasms* / pathology
  • Mice
  • Mice, Nude
  • Mucin-1 / physiology*
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Tumor Escape / genetics*


  • B7-H1 Antigen
  • CD274 protein, human
  • MUC1 protein, human
  • Mucin-1