Redox cross-talk between myeloid-derived suppressor cells and dendritic cells in cancer: accumulation of oxygenated lipid droplets and suppression of antigen cross-presentation

Details

• Personal Author:
  Amoscato A ; Cao W ; Gabrilovich D ; Kagan VE ; Loomen J ; Tyurin VA
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Immune System Lipids Neoplasms Occupational Health Safety Toxicology
• Keywords:
  Cancer Cell-damage Cell-function Cellular-function Immune-system Immunology Molecular-biology Molecular-structure
• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Pages in Document:
  260-261
• Volume:
  138
• Issue:
  1
• NIOSHTIC Number:
  nn:20043905
• Citation:
  Toxicologist 2014 Mar; 138(1):260-261
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  False
• Start Date:
  20050701
• Source Full Name:
  The Toxicologist. Society of Toxicology 53rd Annual Meeting and ToxExpo, March 23-27, 2014, Phonex, Arizona
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:af94db48635ce15cefea02c3adb70ed49c5b662cd14cc9f7a96d065bf3de7e49f776d27acfc7d3f54af738eec6f11405e36a7fb42dd716018483e6830c0157cf
• Download URL:
  https://stacks.cdc.gov/view/cdc/199777/cdc_199777_DS1.pdf
• File Type:
  [PDF - 1.03 MB ]