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

2016; Cell Press; Volume: 29; Issue: 6 Linguagem: Inglês

10.1016/j.ccell.2016.04.014

1878-3686

Colin W. Steele, Saadia A. Karim, Joshua D.G. Leach, Peter J. Bailey, Rosanna Upstill‐Goddard, Loveena Rishi, Mona Foth, Sheila Bryson, Karen McDaid, Zena Wilson, Catherine A. Eberlein, Juliana Candido, Mairi Clarke, Colin Nixon, John Connelly, Nigel B. Jamieson, C. Ross Carter, Frances R. 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,

Immune cells in cancer

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.