Oxidized lipid bodies block antigen cross-presentation in cancer by preventing trafficking of peptide-MHC class I complexes

Abstract

Abstract Background Antigen cross presentation is a unique feature of dendritic cells (DCs) and plays an important role in the development of specific CD8+ T cell responses. It is established that the defect in cross-presentation by dendritic cells (DCs) in cancer results in ineffective antitumor immune responses and favors tumor escape. However, the mechanisms behind this phenomenon are unclear. Results In this study we found that tumor-derived factors impaired cross-presentation by differentiated conventional DCs without affecting expression of MHC class I, class II, or costimulatory molecules. The ability of DCs to stimulate antigen-specific T cells after loading with short peptide (directly bound to MHC class I) was fully preserved. We found that tumor-derived factors blocked trafficking of peptide-MHC class I (pMHC) complexes to the cell surface. These complexes were found to be entrapped into the lysosomes. This effect was caused by the accumulation of lipid bodies (LB) containing oxidized (ox) triglycerides (TAG) in DCs. Importantly LB containing non-oxidized TAG did not affect cross-presentation. Further experiments have identified the specific molecular mechanism responsible for oxTAG containing LB mediated block of cross-presentation in DCs. Conclusions Our results suggest a novel mechanism of regulation of cross-presentation in cancer