Myeloid cells are required for PD-1/PD-L1 checkpoint activation and the establishment of an immunosuppressive environment in pancreatic cancer
Y Zhang, A Velez-Delgado, E Mathew, D Li… - Gut, 2017 - gut.bmj.com
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 …
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 …
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.
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