PMID- 28288138
OWN - NLM
STAT- MEDLINE
DCOM- 20170929
LR  - 20210109
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 36
IP  - 28
DP  - 2017 Jul 13
TI  - MUC1-C integrates PD-L1 induction with repression of immune effectors in 
      non-small-cell lung cancer.
PG  - 4037-4046
LID - 10.1038/onc.2017.47 [doi]
AB  - 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-kappaB (NF-kappaB) 
      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-kappaB p65 occupancy on the CD274/PD-L1 promoter and thereby drives 
      CD274 transcription. Moreover, we demonstrate that MUC1-C-induced activation of 
      NF-kappaB-->︀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.
FAU - Bouillez, A
AU  - Bouillez A
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Rajabi, H
AU  - Rajabi H
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Jin, C
AU  - Jin C
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Samur, M
AU  - Samur M
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Tagde, A
AU  - Tagde A
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Alam, M
AU  - Alam M
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Hiraki, M
AU  - Hiraki M
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Maeda, T
AU  - Maeda T
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Hu, X
AU  - Hu X
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Adeegbe, D
AU  - Adeegbe D
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Kharbanda, S
AU  - Kharbanda S
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Wong, K-K
AU  - Wong KK
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
FAU - Kufe, D
AU  - Kufe D
AD  - Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 
      MA, USA.
LA  - eng
GR  - P50 CA100707/CA/NCI NIH HHS/United States
GR  - R01 CA097098/CA/NCI NIH HHS/United States
GR  - R01 CA166480/CA/NCI NIH HHS/United States
GR  - R21 CA216553/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170313
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (B7-H1 Antigen)
RN  - 0 (CD274 protein, human)
RN  - 0 (MUC1 protein, human)
RN  - 0 (Mucin-1)
SB  - IM
MH  - A549 Cells
MH  - Animals
MH  - B7-H1 Antigen/*genetics
MH  - *Carcinoma, Non-Small-Cell Lung/genetics/immunology/pathology
MH  - Cell Line, Tumor
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Immunity, Cellular/*genetics
MH  - *Lung Neoplasms/genetics/immunology/pathology
MH  - Mice
MH  - Mice, Nude
MH  - Mucin-1/*physiology
MH  - Signal Transduction/genetics/immunology
MH  - Tumor Escape/*genetics
PMC - PMC5509481
MID - NIHMS849355
COIS- CONFLICT OF INTEREST The authors declare competing financial interests; D.K. 
      holds equity in Genus Oncology and is a consultant to the company. The other 
      authors disclosed no potential conflicts of interest.
EDAT- 2017/03/14 06:00
MHDA- 2017/09/30 06:00
PMCR- 2017/09/13
CRDT- 2017/03/14 06:00
PHST- 2016/10/12 00:00 [received]
PHST- 2016/12/15 00:00 [revised]
PHST- 2017/02/01 00:00 [accepted]
PHST- 2017/03/14 06:00 [pubmed]
PHST- 2017/09/30 06:00 [medline]
PHST- 2017/03/14 06:00 [entrez]
PHST- 2017/09/13 00:00 [pmc-release]
AID - onc201747 [pii]
AID - 10.1038/onc.2017.47 [doi]
PST - ppublish
SO  - Oncogene. 2017 Jul 13;36(28):4037-4046. doi: 10.1038/onc.2017.47. Epub 2017 Mar 
      13.