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)

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)

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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:Clarke, Dr Mairi and Bryson, Miss Sheila and Biankin, Professor Andrew and Leach, Dr Joshua and Nixon, Mr Colin and Bailey, Dr Peter and Nibbs, Professor Robert and Strathdee, Dr Douglas and Morton, Dr Jennifer and Upstill-Goddard, Dr Rosanna and Evans, Professor Thomas and Steele, Dr Colin and Chang, Dr 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 > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
571591Investigating the role of CXCR2 in pancreatic inflammation and cancer.Owen SansomWellcome Trust (WELLCOME)096021/Z/11/ZICS - BEATSON INSTITUTE FOR CANCER RES.
647983CR-UK Centre renewalKaren VousdenCancer Research UK (CAN-RES-UK)18076RI CANCER SCIENCES