Abstract 3530: Lipid accumulation inhibits DC ability for cross-presentation of antigens in tumor-bearing mice

Abstract

Abstract Professional antigen presenting cells dendritic cells (DCs) play an important role in the initiation and maintenance of immune responses. Numerous studies have demonstrated defective function of DCs in cancer. However, the mechanisms of those defects remain not clear. Previously, we have demonstrated that DCs in tumor-bearing hosts accumulate lipids via up-regulation of the expression of scavenger receptor A (CD204). This resulted in inability of DCs to effectively process exogenous antigens. In this study we found that the DCs exposed to tumor-derived factors (TDF) in vitro or isolated from tumor-bearing (TB) mice had increased uptake of soluble protein ovalbumin (OVA). No defect in the activity of lysosomal and endosomal proteases was detected. Using mass-spectrometry we determined that TDF did not affect processing of OVA by DCs. At the same time, DCs exposed to TDF or isolated from TB mice expressed lower levels of OVA-derived peptide-MHC class I (pMHC) complexes and decreased ability to stimulate OVA peptide specific CD8+ T cells (OT1). Using lipid mass-spectrometry we found substantial accumulation of oxidized lipids in DCs obtained from TB mice or generated in vitro in the presence of TDF. To mimic accumulation of oxidized lipids in vitro, we treated bone marrow derived DCs with linoleic fatty acid (LA) and oxidized agent azobis-(2,4-dimethylvaleronitrile) (AMVN). DCs easily picked LA and form lipid bodies similar to the process observed in the presence of TDF. However, accumulation of LA did not result in defective processing of OVA-derived epitope as was determined by measuring the level of pMHC on DC surface and by stimulation of OT1 cells. AMVN at selected concentration also did not affect OVA processing and presentation. In contrast, combination of LA and AMVN significantly reduced the ability of DCs to process antigens associated with OVA. No changes in the expression of MHC class I and co-stimulatory molecules were observed. These data indicate that oxidized lipids accumulated in DCs in tumor-bearing hosts prevent cross-presentation of antigens, which may have important implications for DC ability to induce tumor-specific immune responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3530. doi:1538-7445.AM2012-3530