Abstract Myeloid derived suppressor cells (MDSC) play an important role in the regulation of anti-tumor responses and their presence in cancer patients correlates with a poor prognosis. MDSC contribute to the failure of cancer therapies and favor tumor progression and metastasis. However, despite the recent advances in understanding the biology of MDSC, the mechanisms driving their expansion and suppressive function are not yet well defined. Polymorphonuclear, PMN-MDSC is by far the largest population of MDSC. Here, we found that PMN-MDSC from tumor bearing mice and from cancer patients have higher amount of lipids than their counterpart (neutrophils) in tumor free mice and healthy donors, respectively. The content of lipids in PMN-MDSC was much higher in MDSC infiltrating the tumor, and the accumulation of lipids in PMN-MDSC was caused by the uptake of extracellular lipids. Lipid profile of PMN-MDSC demonstrated accumulation of oxidized fatty acids as part of triglycerides and phospholipids. We demonstrated that fatty acids accumulated by PMN-MDSC are oxidized by myeloperoxidase (MPO) and reactive oxygen species (ROS) generated by Nox2. Genetic ablation of MPO or ROS in MDSC results in a drastic reduction of lipid oxidation and in an impaired ability of MDSC to suppress CD8 T cell responses. In line with these findings, unsaturated fatty acids, highly susceptible to oxidation, favor the expansion of highly suppressive MDSC from hematopoietic progenitors in vitro, contrary to non-oxidizable saturated fatty acids. Together, our data suggest that MDSC have increased ability to pick up lipids from the microenvironment and to oxidize them via their potent oxidative machinery. In turn oxygenated lipids contribute to the suppressive activity of MDSC. In conclusion, the regulation of the oxidation of lipids in MDSC could be an attractive therapeutic strategy in cancer. Citation Format: Filippo Veglia, Vladimir A. Tyurin, Valerian E. Kagan, Dmitry Gabrilovich. Lipids and suppressive functions of MDSC in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5133.
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