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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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Cell Press
2016
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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. |
format | Online Article Text |
id | pubmed-4912354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Cell Press |
record_format | MEDLINE/PubMed |
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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