Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma
Authors: Darren R Cullinan
Ryan C Fields
David G DeNardo
Ryan C Jacobs
Booyeon J Han
Brian A Belt
Timothy M Nywening
Dominic E Sanford
Ankit A Patel
David C Linehan
Jian Ye
William G Hawkins
Roheena Z Panni
Peter Goedegebuure
William E Gillanders
Journal: Gut (2018)
Discipline: CLINICAL MEDICINE
Keywords: cytokines; immune response; immunoregulation; inflammatory mechanisms; pancreatic cancer.
Affiliations: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA., Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, USA., Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA., Tumor Biology Program, University of Rochester Medical Center, Rochester, New York, USA., Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA., Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, Missouri, USA., Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Abstract:  Objective: Chemokine pathways are co-opted by pancreatic adenocarcinoma (PDAC) to facilitate myeloid cell recruitment from the bone marrow to establish an immunosuppressive tumour microenvironment (TME). Targeting tumour-associated CXCR2+neutrophils (TAN) or tumour-associated CCR2+ macrophages (TAM) alone improves antitumour immunity in preclinical models. However, a compensatory influx of an alternative myeloid subset may result in a persistent immunosuppressive TME and promote therapeutic resistance. Here, we show CCR2 and CXCR2 combined blockade reduces total tumour-infiltrating myeloids, promoting a more robust antitumour immune response in PDAC compared with either strategy alone. Methods: Blood, bone marrow and tumours were analysed from PDAC patients and controls. Treatment response and correlative studies were performed in mice with established orthotopic PDAC tumours treated with a small molecule CCR2 inhibitor (CCR2i) and CXCR2 inhibitor (CXCR2i), alone and in combination with chemotherapy. Results: A systemic increase in CXCR2+ TAN correlates with poor prognosis in PDAC, and patients receiving CCR2i showed increased tumour-infiltrating CXCR2+ TAN following treatment. In an orthotopic PDAC model, CXCR2 blockade prevented neutrophil mobilisation from the circulation and augmented chemotherapeutic efficacy. However, depletion of either CXCR2+ TAN or CCR2+ TAM resulted in a compensatory response of the alternative myeloid subset, recapitulating human disease. This was overcome by combined CCR2i and CXCR2i, which augmented antitumour immunity and improved response to FOLFIRINOX chemotherapy. Conclusion: Dual targeting of CCR2+ TAM and CXCR2+ TAN improves antitumour immunity and chemotherapeutic response in PDAC compared with either strategy alone. 

Retracted: No

PubPeer comments:
 ![file] There must be an error with fig. 5A-B. a) the values are exactly the same. b) the error bars are exactly the same. c) the y axis title for CD4+ cells bears the name  CD8+ . d) the p values are anyway different. I think that the authors unwillingly copied the CD8 histograms in the CD4 space. ,