Influence of the acidic microenvironment in mesothelioma on dendritic cell function

Details

Supervisors

Feron, Olivier ; Trempolec, Natalia

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences pharmaceutiques

Abstract

By capturing, processing and presenting tumor antigens to T cells, dendritic cells (DC) are the cornerstone of the anti-tumor immune response. However, the tumor microenvironment complicates the task of DCs, making them less capable of activating T cells in part by promoting the accumulation of intracellular lipids. The origin of this alteration of lipid metabolism in DC is, however, largely unexplored. The recent discovery of the ability of tumor acidosis to induce the formation of lipid droplets under the control of the immunosuppressive cytokine TGF-B2 has therefore led to initiate the present study. This work was conducted in the specific context of mesothelioma, a type of tumor known for its ability to evade the immune system. We examined the effect of conditioned media derived from murine mesothelioma cell lines adapted to acidic pH (6.5) or maintained at physiological pH (7.4) on bone marrow-derived DC. We found that acidosis promotes the production of TGF-B2 by mesothelioma cells and the subsequent formation of lipid droplets in the DC. Although the phagocytosis capacity was slightly increased, all other parameters indicated a loss of DC functionality in response to the acidic conditioned medium, including a deficit of maturation and migration. A strong reduction in CCR7 chemokine receptor expression could indeed be identified in DC exposed to the acidic conditioned medium as well as a significant functional deficit in migration determined in a dedicated in vitro assay. These latter alterations are corrected by administration of a TGF-B receptor inhibitor and reproduced by recombinant TGF-B2 under physiological (non-acidic) conditions. Interestingly, inhibition of the DGAT enzyme (which ensures the last step of triglyceride synthesis and therefore actively participates in the formation of lipid droplets) is able to correct the deficiency in CCR7 expression, thus opening the door to a new therapeutic approach. In conclusion, our work suggests that tumor acidosis could represent a key stimulus in the accumulation of lipid droplets by DC. This observation provides an additional explanation for the immunosuppressive potential of TGF-B2 which, by promoting fatty acid storage in DC, makes them less able to leave the tumor environment and thus to activate T lymphocytes.