Lipid Accumulation and Dendritic Cell Function in Cancer (49.10)

Abstract

Abstract Immune cell dysfunction in cancer is an area of intense study, with particular focus on dendritic cell (DC) abnormalities. The mechanism of these abnormalities remains unclear. We examined the potential role of lipid metabolism in defective DC function in cancer. Different mouse tumor models (CT26, MC38, or EL4) were used for in vivo studies. Tumors grew for up to 3w and then spleens were harvested for DC analysis. Phenotypic analysis by flow cytometry included CD11c, CD11b, MHCII, CD40, CD80, and CD86. Lipid levels were determined using Bodipy 493/503. For the analysis of DC function, cells with high and normal lipid content were sorted and used in allogenic mixed leukocyte reaction. For in vitro studies, DCs were harvested from spleen and cultured overnight with a variety of stimulants (LPS, tumor supernatant, GM-CSF, or IL-4). The control level of lipids in DCs was established in naïve tumor-free mice. 30–40% of freshly isolated splenic DCs from tumor-bearing mice had increased levels of intracellular lipid compared to naïve mice, and this accumulation was time dependent. Phenotypically, DCs with increased amounts of lipid had increased levels of MHCII and co-stimulatory molecules. However, despite that increase, DCs with high lipid content had substantially reduced ability to stimulate T cells in allogenic mixed leukocyte reaction than DCs with normal lipid amount. These results indicate a role for lipid accumulation in dendritic cell dysfunction. The data also indicate that the tumor microenvironment is necessary to induce the lipid accumulation and dysfunction.