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PMID: 27265504 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Cancer cell ·Vol. 29 ·No. 6 ·2016-00-13 ·Pages 832-845

Steele CW, Karim SA, Leach JDG, Bailey P, Upstill-Goddard R, Rishi L, Foth M, Bryson S, McDaid K, Wilson Z, Eberlein C, Candido JB, Clarke M, Nixon C, Connelly J, Jamieson N, Carter CR, Balkwill F, Chang DK, Evans TRJ, Strathdee D, Biankin AV, Nibbs RJB, Barry ST, Sansom OJ, Morton JP

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.

MeSH Terms
Animals Antibodies, Monoclonal/administration & dosage,pharmacology Antibodies, Monoclonal, Humanized Carcinoma, Pancreatic Ductal/drug therapy,genetics,pathology Cell Line, Tumor Deoxycytidine/administration & dosage,analogs & derivatives,pharmacology Gene Expression Regulation, Neoplastic/drug effects Humans Immunotherapy Mice Neoplasm Metastasis Pancreatic Neoplasms/drug therapy,genetics,pathology Prognosis Receptors, Interleukin-8B/antagonists & inhibitors,genetics Signal Transduction Small Molecule Libraries/administration & dosage,pharmacology Survival Analysis Up-Regulation Xenograft Model Antitumor Assays
Chemicals
Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Receptors, Interleukin-8B Small Molecule Libraries Deoxycytidine atezolizumab gemcitabine
Authors & Affiliations
26 authors, click to expand affiliations / ORCID
Steele Colin W
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Karim Saadia A
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Leach Joshua D G
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Bailey Peter
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Upstill-Goddard Rosanna
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Rishi Loveena
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Foth Mona
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Bryson Sheila
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
McDaid Karen
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Wilson Zena
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Eberlein Catherine
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Candido Juliana B
Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK.
Clarke Mairi
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK.
Nixon Colin
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Connelly John
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Jamieson Nigel
Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
Carter C Ross
Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
Balkwill Frances
Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK.
Chang David K
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Evans T R Jeffry
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Strathdee Douglas
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Biankin Andrew V
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Nibbs Robert J B
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK.
Barry Simon T
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Sansom Owen J
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.
Morton Jennifer P
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccell.2016.04.014
Email
o.sansom@beatson.gla.ac.uk
Published
2016-00-13
Epub
2016-00-02
Pages
832-845
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC4912354
Subset
IM
Grants
Cancer Research UK · 11650 · United Kingdom
Cancer Research UK · 12946 · United Kingdom
Pancreatic Cancer UK · FLF2015_04_GLASGOW · United Kingdom
Medical Research Council · G0900992 · United Kingdom
Corrections
CommentIn
PMID: 27300430
External Links
PubMed source DOI: 10.1016/j.ccell.2016.04.014 PMC Full Text View journal details
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