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

Colin W Steele; Saadia A Karim; Joshua D G Leach; Peter Bailey; Rosanna Upstill-Goddard; Loveena Rishi; Mona Foth; Sheila Bryson; Karen McDaid; Zena Wilson; Catherine Eberlein; Juliana B Candido; Mairi Clarke; Colin Nixon; John Connelly; Nigel Jamieson; C Ross Carter; Frances Balkwill; David K Chang; T R Jeffry Evans; Douglas Strathdee; Andrew V Biankin; Robert J B Nibbs; Simon T Barry; Owen J Sansom; Jennifer P Morton

doi:10.1016/j.ccell.2016.04.014

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

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

Authors

Colin W Steele¹, Saadia A Karim¹, Joshua D G Leach¹, Peter Bailey², Rosanna Upstill-Goddard², Loveena Rishi², Mona Foth¹, Sheila Bryson¹, Karen McDaid³, Zena Wilson³, Catherine Eberlein³, Juliana B Candido⁴, Mairi Clarke⁵, Colin Nixon¹, John Connelly¹, Nigel Jamieson⁶, C Ross Carter⁶, Frances Balkwill⁴, David K Chang², T R Jeffry Evans⁷, Douglas Strathdee¹, Andrew V Biankin², Robert J B Nibbs⁵, Simon T Barry³, Owen J Sansom⁸, Jennifer P Morton⁷

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies, Monoclonal / administration & dosage*
Antibodies, Monoclonal / pharmacology
Antibodies, Monoclonal, Humanized
Carcinoma, Pancreatic Ductal / drug therapy*
Carcinoma, Pancreatic Ductal / genetics
Carcinoma, Pancreatic Ductal / pathology
Cell Line, Tumor
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Gemcitabine
Gene Expression Regulation, Neoplastic / drug effects
Humans
Immunotherapy
Mice
Neoplasm Metastasis
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / pathology
Prognosis
Receptors, Interleukin-8B / antagonists & inhibitors
Receptors, Interleukin-8B / genetics*
Signal Transduction
Small Molecule Libraries / administration & dosage
Small Molecule Libraries / pharmacology
Survival Analysis
Up-Regulation
Xenograft Model Antitumor Assays

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Receptors, Interleukin-8B
Small Molecule Libraries
Deoxycytidine
atezolizumab
Gemcitabine

Abstract

Publication types

MeSH terms

Substances

Grants and funding