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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Vydáno v:	Cancer cell Ročník 29; číslo 6; s. 832
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 13.06.2016
Témata:	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
On-line přístup:	Zjistit podrobnosti o přístupu
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Shrnutí:	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.
Bibliografie:	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