CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype

被引：181

作者：

Candido, Juliana B. ^{[1
]}

Morton, Jennifer P. ^{[2
,3
]}

Bailey, Peter ^{[3
]}

Campbell, Andrew D. ^{[2
]}

Karim, Saadia A. ^{[2
]}

Jamieson, Thomas ^{[2
]}

Lapienyte, Laura ^{[2
]}

Gopinathan, Aarthi ^{[4
]}

Clark, William ^{[2
]}

McGhee, Ewan J. ^{[2
]}

Wang, Jun ^{[1
]}

Escorcio-Correia, Monica ^{[1
]}

Zollinger, Raphael ^{[1
]}

Roshani, Rozita ^{[1
]}

Drew, Lisa ^{[5
]}

Rishi, Loveena ^{[3
]}

Arkell, Rebecca ^{[1
]}

Evans, T. R. Jeffry ^{[2
,3
]}

Nixon, Colin ^{[2
]}

Jodrell, Duncan I. ^{[4
]}

Wilkinson, Robert W. ^{[6
]}

Biankin, Andrew V. ^{[3
]}

Barry, Simon T. ^{[7
]}

Balkwill, Frances R. ^{[1
]}

Sansom, Owen J. ^{[2
,3
]}

机构：

[1] Queen Mary Univ London, Barts Canc Inst, London EC1M 6BQ, England

[2] Canc Res UK Beatson Inst, Glasgow G61 1BD, Lanark, Scotland

[3] Univ Glasgow, Inst Canc Sci, Glasgow G61 1QH, Lanark, Scotland

[4] Univ Cambridge, Li Ka Shing Ctr, Canc Res UK Cambridge Inst, Robinson Way, Cambridge CB2 0RE, England

[5] AstraZeneca, IMED Biotech Unit, Oncol, Biosci, Boston, MA USA

[6] MedImmune Ltd, Granta Pk, Cambridge CB21 6GH, England

[7] AstraZeneca, IMED Biotech Unit, Oncol, Biosci, Cambridge, England

来源：

CELL REPORTS | 2018年 / 23卷 / 05期

关键词：

DUCTAL ADENOCARCINOMA; MYELOID CELLS; MOUSE MODEL; CANCER; FIBROBLASTS; INHIBITION; BLOCKADE; IMMUNOTHERAPY; RESPONSES; EFFICACY;

D O I：

10.1016/j.celrep.2018.03.131

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors.

引用

页码：1448 / 1460

页数：13

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