CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Jun 7

PMID 27265504

Citations 476

Authors

Colin W Steele

Saadia A Karim

Joshua D G Leach

Peter Bailey

Rosanna Upstill-Goddard

Loveena Rishi

Mona Foth

Sheila Bryson

Karen McDaid

Zena Wilson

Catherine Eberlein

Juliana B Candido

Mairi Clarke

Colin Nixon

John Connelly

Nigel Jamieson

C Ross Carter

Frances Balkwill

David K Chang

T R Jeffry Evans

Douglas Strathdee

Andrew V Biankin

Robert J B Nibbs

Simon T Barry

Owen J Sansom

Jennifer P Morton

Affiliations

Soon will be listed here.

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.

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