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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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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912354/
https://www.ncbi.nlm.nih.gov/pubmed/27265504
http://dx.doi.org/10.1016/j.ccell.2016.04.014
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author 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.
author_facet 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.
author_sort Steele, Colin W.
collection PubMed
description 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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spelling pubmed-49123542016-06-26 CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma 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. Cancer Cell Article 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. Cell Press 2016-06-13 /pmc/articles/PMC4912354/ /pubmed/27265504 http://dx.doi.org/10.1016/j.ccell.2016.04.014 Text en © 2016 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
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.
CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title_full CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title_fullStr CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title_full_unstemmed CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title_short CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma
title_sort cxcr2 inhibition profoundly suppresses metastases and augments immunotherapy in pancreatic ductal adenocarcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4912354/
https://www.ncbi.nlm.nih.gov/pubmed/27265504
http://dx.doi.org/10.1016/j.ccell.2016.04.014
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