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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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

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Mucin-1
Non-Small Cell Lung Carcinoma
Toll-Like Receptor 9
Immune Evasion
Chemokine CCL2
Adaptive Immunity
Granulocyte-Macrophage Colony-Stimulating Factor
Innate Immunity
Genes
Up-Regulation
Ligands
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Bouillez, A., Rajabi, H., Jin, C., Samur, M., Tagde, A., Alam, M., ... 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

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

In: Oncogene, Vol. 36, No. 28, 13.07.2017, p. 4037-4046.

Research output: Contribution to journalArticle

Bouillez, A, Rajabi, H, Jin, C, Samur, M, Tagde, A, Alam, M, Hiraki, M, Maeda, T, Hu, X, Adeegbe, D, Kharbanda, S, Wong, KK & Kufe, D 2017, 'MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer', Oncogene, vol. 36, no. 28, pp. 4037-4046. https://doi.org/10.1038/onc.2017.47
Bouillez A, Rajabi H, Jin C, Samur M, Tagde A, Alam M et al. 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. https://doi.org/10.1038/onc.2017.47
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. / MUC1-C integrates PD-L1 induction with repression of immune effectors in non-small-cell lung cancer. In: Oncogene. 2017 ; Vol. 36, No. 28. pp. 4037-4046.
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