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Gut. 2018 Jun;67(6):1112-1123. doi: 10.1136/gutjnl-2017-313738. Epub 2017 Dec 1.

Targeting both tumour-associated CXCR2+ neutrophils and CCR2+ macrophages disrupts myeloid recruitment and improves chemotherapeutic responses in pancreatic ductal adenocarcinoma.

Author information

1
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Alvin J Siteman Cancer Center, Washington University School of Medicine, St Louis, Missouri, USA.
3
Department of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
4
Tumor Biology Program, University of Rochester Medical Center, Rochester, New York, USA.
5
Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA.
6
Department of Medicine, Oncology Division, Washington University School of Medicine, St. Louis, Missouri, USA.
7
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.

KEYWORDS:

cytokines; immune response; immunoregulation; inflammatory mechanisms; pancreatic cancer

PMID:
29196437
PMCID:
PMC5969359
DOI:
10.1136/gutjnl-2017-313738
[Indexed for MEDLINE]
Free PMC Article

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