ITOC2 – 008. Melanoma differentiation-associated protein 5 (MDA5)-based tumour immunotherapy reprograms M2/G2-polarised myeloid-derived suppressor cells (MDSCs)

Abstract

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.