Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer
Top Cited Papers
Open Access
- 8 July 2016
- Vol. 66 (1), 124-136
- https://doi.org/10.1136/gutjnl-2016-312078
Abstract
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 pre-established 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 anti-tumour 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.Keywords
Funding Information
- National Institute of Diabetes and Digestive and Kidney Diseases (NIH T32 DK094775)
- National Cancer Institute (K08 CA138907, NCI P30CA046592, NCI-1R01CA151588-01)
- National Institute of General Medical Sciences (NIH T32 GM007315)
- American Cancer Society
This publication has 53 references indexed in Scilit:
- Metastatic Pancreatic Cancer Is Dependent on Oncogenic Kras in MicePLOS ONE, 2012
- EGF Receptor Signaling Is Essential for K-Ras Oncogene-Driven Pancreatic Ductal AdenocarcinomaCancer Cell, 2012
- Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced CancerThe New England Journal of Medicine, 2012
- Tumor-Derived Granulocyte-Macrophage Colony-Stimulating Factor Regulates Myeloid Inflammation and T Cell Immunity in Pancreatic CancerCancer Cell, 2012
- Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in miceJCI Insight, 2012
- Stat3 and MMP7 Contribute to Pancreatic Ductal Adenocarcinoma Initiation and ProgressionCancer Cell, 2011
- CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and HumansScience, 2011
- β-catenin blocks Kras-dependent reprogramming of acini into pancreatic cancer precursor lesions in miceJCI Insight, 2010
- Conditional and inducible transgene expression in mice through the combinatorial use of Cre-mediated recombination and tetracycline inductionNucleic Acids Research, 2005
- Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunityNature Reviews Immunology, 2004