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 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.
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Colin W
CW
Steele
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Saadia A
SA
Karim
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Joshua D G
JDG
Leach
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Peter
P
Bailey
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Rosanna
R
Upstill-Goddard
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Loveena
L
Rishi
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Mona
M
Foth
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Sheila
S
Bryson
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Karen
K
McDaid
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Zena
Z
Wilson
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Catherine
C
Eberlein
Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK.
Juliana B
JB
Candido
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK.
Mairi
M
Clarke
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Colin
C
Nixon
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
John
J
Connelly
Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
Nigel
N
Jamieson
Department of Surgery, Glasgow Royal Infirmary, Glasgow G4 0SF, UK.
C Ross
CR
Carter
Centre for Cancer and Inflammation, Barts Cancer Institute, London EC1M 6BQ, UK.
Frances
F
Balkwill
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
David K
DK
Chang
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
T R Jeffry
TRJ
Evans
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK.
Douglas
D
Strathdee
Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Andrew V
AV
Biankin
Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow G12 8QQ UK.
Robert J B
RJB
Nibbs
Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
Simon T
ST
Barry
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.
Owen J
OJ
Sansom
Cancer Research UK Beatson Institute, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1BD, UK.
Jennifer P
JP
Morton
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy; D051379:Mice; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000008:administration & dosage / Q000494:pharmacology; D016019:Survival Analysis; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D023063:Receptors, Interleukin-8B; D054852:Small Molecule Libraries; D003841:Deoxycytidine; C000594389:atezolizumab; D000093542:Gemcitabine