Abstract
Abstract MDSCs are a heterogeneous population of cells that consists of myeloid progenitor cells and immature myeloid cells (IMCs). In healthy individuals, IMCs that are generated in the bone marrow quickly differentiate into mature granulocytes, macrophages or dendritic cells (DCs). By contrast, under pathological conditions, such as cancer, a partial block in the differentiation of IMCs and activation of these cells results in the expansion of the population with potent immune suppressive activity – myeloid-derived suppressor cells. We investigated the mechanism of MDSC effect on immune system and focused our attention on possible role of fatty acids (FA) in this process. Recently, we found FA accumulation in dendritic cells (DCs) from tumor bearing mice or cancer patients. It was caused by increased uptake of extracellular lipids due to up-regulation of scavenger receptor A. FA accumulation in DCs resulted in the dysfunction of DCs. Pharmacological normalization of lipid abundance in DCs with an inhibitor of acetyl-CoA carboxylase restored the functional activity of DCs and substantially enhanced the effects of cancer vaccines. In parallel, we also observed dramatic lipid accumulation in MDSC from tumor bearing mice. Interestingly, MDSCs don't have up-regulation of scavenger receptor A, but instead have increased expression of fatty acid transporter FATP4. Over-expression of FATP4 in MDSCs induced lipid accumulation. This suggested that FATP4 may be involved in the accumulation of lipid in these cells. MDSCs with lipid overload exerted stronger inhibitory effect on immune cells than MDSC with normal lipid level. MDSCs treated with unsaturated FA linoleic acid displayed stronger inhibitory effect than MDSCs treated with saturated FA palmitic acid. Since MDSCs has strong oxidizing environment, the data suggested that oxidized FA may be involved in the inhibitory effect of MDSCs. Elucidation of this mechanism in detail will be helpful for the development of potential therapeutic targets regulating immune function in tumor-bearing hosts. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3649. doi:10.1158/1538-7445.AM2011-3649
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