Redox cross-talk between myeloid-derived suppressor cells and dendritic cells in cancer: accumulation of oxygenated lipid droplets and suppression of antigen cross-presentation.
Tyurin-VA; Cao-W; Amoscato-A; Loomen-J; Gabrilovich-D; Kagan-VE
Toxicologist 2014 Mar; 138(1):260-261
Accumulation of myeloid-derived suppressor cells (MDSCs), and expansion of immature dendritic cells (DCs) with aberrant cross-presentation - are important immunological abnormalities in cancer. While interactions between these cells are recognized as contributors to the failed anti-tumor immunity, their molecular mechanisms remain elusive. Excessive formation of lipid droplets (LDs) affects DC's immune functions. We show that DCs from tumor-bearing mice or treated with tumor explant supernatants (EL4, MC38) contained oxygenated neutral lipids: triglycerides (oxTAGs), free fatty acids (oxFFAs) and cholesterol esters (oxCE). LC-ESI-MS/MS revealed that oxTAGs were represented by a spectrum of truncated molecular species 39:1; 39:0; 41:1; 41:0; 43:2; 43:1; 43:0 and 45:2 with 9-oxo-nonanoic and 7-oxo-heptanoic acids. We hypothesized that MDSC - with their high ROS and myeloperoxidase activity - might be a source of oxygenated lipids. To test this, DCs were co-cultured with MDSC (Gr-1+,C57BL6 BM, pre-cultured with GM-CSF and deuterated linoleic acid, LA-d4) followed by purification of DCs from the mixture of cells. We found that LA-d4 was incorporated into TAGs and several classes of phospholipids in MDSC and DC. Further, we demonstrated the transfer of LA-d4 from pre-loaded MDSC to DCs whereby increased amounts of oxFFAs and oxTAGs, including truncated TAGs, were identified. In contrast, no oxidized phospholipids were observed in either MDSC or DCs. By using a lipid-soluble radical azo-initiator, AMVN, we bolstered oxidation of LDs of LA-supplemented DCs and showed that accumulation of oxidized neutral lipids inhibited antigen cross-presentation. This suggests a novel role for oxidized lipids in immune responses - as regulators of antigen cross-presentation.
Toxicology; Cell-function; Cellular-function; Cell-damage; Immunology; Immune-system; Cancer; Molecular-biology; Molecular-structure; Lipids
The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona
University of Pittsburgh at Pittsburgh