期刊
GUT
卷 66, 期 1, 页码 124-136出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/gutjnl-2016-312078
关键词
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资金
- University of Michigan Biological Scholar Program
- University of Michigan Cancer Center Support Grant [NCI P30CA046592]
- American Cancer Society
- Elsa U Pardee Foundation
- University of Michigan Program in Cellular and Molecular Biology training grant [NIH T32 GM007315]
- University of Michigan Gastrointestinal Training Grant [NIH T32 DK094775]
- National Institutes of Health [K08 CA138907]
- [NCI-1R01CA151588-01]
- NATIONAL CANCER INSTITUTE [R01CA151588, K08CA138907, P30CA046592, R01CA198074] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [T32DK094775] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007315, R25GM086262] Funding Source: NIH RePORTER
Background Pancreatic cancer is characterised by the accumulation of a fibro-inflammatory stroma. Within this stromal reaction, myeloid cells are a predominant population. Distinct myeloid subsets have been correlated with tumour promotion and unmasking of anti-tumour immunity. Objective The goal of this study was to determine the effect of myeloid cell depletion on the onset and progression of pancreatic cancer and to understand the relationship between myeloid cells and T cell-mediated immunity within the pancreatic cancer microenvironment. Methods Primary mouse pancreatic cancer cells were transplanted into CD11b-diphtheria toxin receptor (DTR) mice. Alternatively, the iKras* mouse model of pancreatic cancer was crossed into CD11b-DTR mice. CD11b(+) cells (mostly myeloid cell population) were depleted by diphtheria toxin treatment during tumour initiation or in established tumours. Results Depletion of myeloid cells prevented KrasG12D-driven pancreatic cancer initiation. In preestablished tumours, myeloid cell depletion arrested tumour growth and in some cases, induced tumour regressions that were dependent on CD8(+) T cells. We found that myeloid cells inhibited CD8(+) T-cell antitumour activity by inducing the expression of programmed cell death-ligand 1 (PD-L1) in tumour cells in an epidermal growth factor receptor (EGFR)/mitogen-activated protein kinases (MAPK)-dependent manner. Conclusion Our results show that myeloid cells support immune evasion in pancreatic cancer through EGFR/MAPK-dependent regulation of PD-L1 expression on tumour cells. Derailing this crosstalk between myeloid cells and tumour cells is sufficient to restore anti-tumour immunity mediated by CD8(+) T cells, a finding with implications for the design of immune therapies for pancreatic cancer.
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