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

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 abroga...

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Veröffentlicht in:Cancer cell Jg. 29; H. 6; S. 832
Hauptverfasser: Steele, Colin W, Karim, Saadia A, Leach, Joshua D G, Bailey, Peter, Upstill-Goddard, Rosanna, Rishi, Loveena, Foth, Mona, Bryson, Sheila, McDaid, Karen, Wilson, Zena, Eberlein, Catherine, Candido, Juliana B, Clarke, Mairi, Nixon, Colin, Connelly, John, Jamieson, Nigel, Carter, C Ross, Balkwill, Frances, Chang, David K, Evans, T R Jeffry, Strathdee, Douglas, Biankin, Andrew V, Nibbs, Robert J B, Barry, Simon T, Sansom, Owen J, Morton, Jennifer P
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 13.06.2016
Schlagworte:
Animals
Antibodies, Monoclonal - administration & dosage
Antibodies, Monoclonal - pharmacology
Antibodies, Monoclonal, Humanized
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Deoxycytidine - administration & dosage
Deoxycytidine - analogs & derivatives
Deoxycytidine - pharmacology
Gemcitabine
Gene Expression Regulation, Neoplastic - drug effects
Humans
Immunotherapy
Mice
Neoplasm Metastasis
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - genetics
Pancreatic Neoplasms - pathology
Prognosis
Receptors, Interleukin-8B - antagonists & inhibitors
Receptors, Interleukin-8B - genetics
Signal Transduction
Small Molecule Libraries - administration & dosage
Small Molecule Libraries - pharmacology
Survival Analysis
Up-Regulation
Xenograft Model Antitumor Assays
ISSN:1878-3686, 1878-3686
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Zusammenfassung: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.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2016.04.014