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Cancer Cell. 2016 Jun 13;29(6):832-845. doi: 10.1016/j.ccell.2016.04.014. Epub 2016 Jun 2.

CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma.

Author information

1
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
2
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
3
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
4
Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK.
5
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK.
6
Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
7
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
8
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: o.sansom@beatson.gla.ac.uk.

Abstract

CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target.

PMID:
27265504
PMCID:
PMC4912354
DOI:
10.1016/j.ccell.2016.04.014
[Indexed for MEDLINE]
Free PMC Article

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