CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma

Steele, C. W. et al. (2016) CXCR2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma. Cancer Cell, 29(6), pp. 832-845. (doi: 10.1016/j.ccell.2016.04.014) (PMID:27265504) (PMCID:PMC4912354)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Jamieson, Professor Nigel and Bailey, Dr Peter and Nibbs, Professor Rob and Clarke, Dr Mairi and Bryson, Miss Sheila and Upstill-Goddard, Dr Rosie and Biankin, Professor Andrew and Leach, Dr Joshua and Nixon, Mr Colin and Evans, Professor Jeff and Steele, Dr Colin and Morton, Professor Jen and Strathdee, Mr Douglas and Chang, Professor David and Karim, Ms Saadia and Sansom, Professor Owen
• Authors: Steele, C. W., Karim, S. A., Leach, J. D.G., Bailey, P., Upstill-Goddard, R., Rishi, L., Foth, M., Bryson, S., McDaid, K., Wilson, Z., Eberlein, C., Candido, J., Clarke, M., Nixon, C., Connelly, J., Jamieson, N., Carter, R., Balkwill, F., Chang, D., Evans, T.R. J., Strathdee, D., Biankin, A. V., Nibbs, R. J.B., Barry, S. T., Sansom, O. J., and Morton, J. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Virus Research
• Journal Name: Cancer Cell
• Publisher: Elsevier
• ISSN: 1535-6108
• ISSN (Online): 1878-3686
• Published Online: 02 June 2016
• Copyright Holders: Copyright © 2016 The Authors
• First Published: First published in Cancer Cell 29(6):832-845
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
57159	1	Investigating the role of CXCR2 in pancreatic inflammation and cancer.	Owen Sansom	Wellcome Trust (WELLCOME)	096021/Z/11/Z	ICS - BEATSON INSTITUTE FOR CANCER RES.
64798	3	CR-UK Centre renewal	Karen Vousden	Cancer Research UK (CAN-RES-UK)	18076	RI CANCER SCIENCES