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Background
Pancreatic cancer shows a dense infiltration of immature myeloid cells including myeloid-derived
suppressor cells (MDSCs). In the tumour, MDSCs polarise in alternatively activated
M2/G2 cells, suppressing T cell responses. We previously reported that RNA-based immunotherapy
with ligands for the cytosolic helicase MDA5 leads to type I interferon (IFN)-driven
tumour immune control in mice with pancreatic cancer. Here we investigated the impact
of MDA5 on MDSC functional profiles.
Methods
Tumour bearing mice were injected intravenous (i.v.) with poly(I:C)-PEI. G-MDSCs (CD11b+Gr-1high)
and M-MDSCs (CD11b+Gr-1intLy6C+) from tumours and spleen were isolated for flow cytometry,
gene expression analysis and suppression assays. Therapeutic efficacy was assessed
in orthotopic tumour models (Panc02, T110299).
Results
Tumour MDSCs exhibit an immunosuppressive phenotype with high levels of PD-L1, TGF-b,
vascular endothelial growth factor (VEGF) and arginase. MDA5 ligands significantly
reduced expression levels of TGFb, arginase, Adam17, galectin-9, as well as STAT3
and STAT5b, indicative of a switch from M2/G2 towards M1/G1 differentiation. This
correlated with reduced suppressive function in T cell assays. Moreover, treatment
led to MDSC apoptosis in vivo and significantly prolonged survival in mice with pancreatic
cancer.
Conclusion
Functional reprograming of MDSCs with MDA5 ligands is a promising strategy for counteracting
immunosuppression in pancreatic cancer.
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