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.
- pancreatic cancer
- inflammatory mechanisms
- immune response
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Contributors TMN, BAB, SPG and DCL designed the study. TMN, BAB, DRC, RZP, BJH, DES, RCJ, JY and AAP performed experiments and conducted analysis. RCF, WGH and DCL assisted in operative specimen collection. RCF, WEG, DGD, WGH and DCL provided funding support, assistance with experimental design and edited the manuscript. TMN wrote the manuscript with input from all authors.
Funding TMN, DRC, RZP and DES recognise support from the NIH T32 CA 009621 training grant in Surgical Oncology (awarded to WEG). BAB, BJH, JY, AAP and DCL acknowledge funding from the NIH 5R01CA168863 and the Pancreatic Cancer Action Network (PANCAN) Translational ResearchGrant (15-65-25 LINE). TMN, DRC, SPG and WGH also recognise support from the Pancreatic Action Network (16-65-Hawk) Translational Research Grant (16-65-Hawk). TMN, DRC, RCF, DGD, SPG and WGH recognise support from the Siteman Cancer Center Frontier Fund. TMN, BAB, DRC, WEG, DGD, DCL and WGH recognise funding from the NCI/NIH Specialized Programs of Research Excellence (SPORE) grant (1P50CA196510). Work supported in part by a research grant to DCL through the Pfizer/Washington University School of Medicine Biomedical Collaborative.
Competing interests None declared.
Ethics approval IRB.
Provenance and peer review Not commissioned; externally peer reviewed.
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