The Role of Free Fatty Acid on Modulating Regulatory Phenotype of MDSC

Myeloid-derived suppressor cells (MDSCs) represent a heterogeneous group of cells that expand during cancer and inflammation, have been reported to modulate cytokine production of macrophages, suppress T-cell response, and promote tumor angiogenesis, tumor cell invasion and metastasis. An accumulation of MDSC in peripheral blood can be observed both in cancer and chronic inflammation, including Inflammatory Bowel Disease and Colon Cancer, while the mechanism of modulating MDSC inhibition is still unclear.

       Here we use the MDSCs cell line MSC-2 to describe a possible cellular mechanism for functional regulation of MDSCs. We found that not only IL-4, but also oleate, an unsaturated fatty acid, can induce a regulatory phenotype in these cells, paralleled by an increase in intracellular lipid droplet accumulation. Furthermore, this inhibitory effect can be reversed by treatment with TOFA, an inhibitor of droplet formation. We compared the ability of oleate (C18:1) and stearate (C18:0) to induce the regulatory phenotype of MDSCs. Our results demonstrate that both fatty acids can induce droplet formation while only oleate treated MSC-2 cells exhibit a suppressive ability. Analysis of nitric oxide (NO) production indicates that the oleate induced regulatory phenotype is mediated by NO and that the effect of oleate can be neutralized by L-NMMA, a non-selective inhibitor of NO synthetase. Thus we suggest a novel unsaturated fatty acid-dependent pathway to regulate formation of MDSCs, a mechanism which will inspire us a novel strategy for anti-tumor therapy.