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 |
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| Format: | Journal Article |
| Sprache: | Englisch |
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United States
13.06.2016
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| ISSN: | 1878-3686, 1878-3686 |
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| Abstract | 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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| AbstractList | 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. 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.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. |
| Author | Sansom, Owen J Carter, C Ross Clarke, Mairi Connelly, John Foth, Mona Eberlein, Catherine Leach, Joshua D G Rishi, Loveena Morton, Jennifer P Bailey, Peter Karim, Saadia A Chang, David K Upstill-Goddard, Rosanna Evans, T R Jeffry Biankin, Andrew V Strathdee, Douglas Bryson, Sheila Nixon, Colin McDaid, Karen Nibbs, Robert J B Wilson, Zena Jamieson, Nigel Balkwill, Frances Barry, Simon T Steele, Colin W Candido, Juliana B |
| Author_xml | – sequence: 1 givenname: Colin W surname: Steele fullname: Steele, Colin W organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 2 givenname: Saadia A surname: Karim fullname: Karim, Saadia A organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 3 givenname: Joshua D G surname: Leach fullname: Leach, Joshua D G organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 4 givenname: Peter surname: Bailey fullname: Bailey, Peter organization: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 5 givenname: Rosanna surname: Upstill-Goddard fullname: Upstill-Goddard, Rosanna organization: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 6 givenname: Loveena surname: Rishi fullname: Rishi, Loveena organization: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 7 givenname: Mona surname: Foth fullname: Foth, Mona organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 8 givenname: Sheila surname: Bryson fullname: Bryson, Sheila organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 9 givenname: Karen surname: McDaid fullname: McDaid, Karen organization: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK – sequence: 10 givenname: Zena surname: Wilson fullname: Wilson, Zena organization: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK – sequence: 11 givenname: Catherine surname: Eberlein fullname: Eberlein, Catherine organization: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK – sequence: 12 givenname: Juliana B surname: Candido fullname: Candido, Juliana B organization: Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK – sequence: 13 givenname: Mairi surname: Clarke fullname: Clarke, Mairi organization: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK – sequence: 14 givenname: Colin surname: Nixon fullname: Nixon, Colin organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 15 givenname: John surname: Connelly fullname: Connelly, John organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 16 givenname: Nigel surname: Jamieson fullname: Jamieson, Nigel organization: Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK – sequence: 17 givenname: C Ross surname: Carter fullname: Carter, C Ross organization: Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK – sequence: 18 givenname: Frances surname: Balkwill fullname: Balkwill, Frances organization: Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK – sequence: 19 givenname: David K surname: Chang fullname: Chang, David K organization: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 20 givenname: T R Jeffry surname: Evans fullname: Evans, T R Jeffry organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 21 givenname: Douglas surname: Strathdee fullname: Strathdee, Douglas organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK – sequence: 22 givenname: Andrew V surname: Biankin fullname: Biankin, Andrew V organization: Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK – sequence: 23 givenname: Robert J B surname: Nibbs fullname: Nibbs, Robert J B organization: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK – sequence: 24 givenname: Simon T surname: Barry fullname: Barry, Simon T organization: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK – sequence: 25 givenname: Owen J surname: Sansom fullname: Sansom, Owen J email: o.sansom@beatson.gla.ac.uk organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK. Electronic address: o.sansom@beatson.gla.ac.uk – sequence: 26 givenname: Jennifer P surname: Morton fullname: Morton, Jennifer P organization: Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/27265504$$D View this record in MEDLINE/PubMed |
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| Snippet | CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic... |
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| SubjectTerms | 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 |
| Title | CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma |
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