Tackling arachidonic acid metabolism in macrophages to overcome immunesuppression and immunotherapy resistance

Tumor metabolism has gained a lot of interest in the last years and, in the immunology field, it became clear that metabolic modulations can play an important role in shaping the immune response towards cancer cells. To identify metabolic features that can be associated with immunotherapy resistance we performed a meta-analysis of transcriptomic and metabolomic data sets. The bicarbonate-importer Slc4a4 and an enzyme involved in arachidonic acid (AA) metabolism were amongst the most upregulated genes associated with unresponsiveness to immune checkpoint inhibitors, raising the question whether these two metabolic pathways were involved in building immunotherapy resistance. Previous work from the host laboratory has provided evidence that genetic targeting of Slc4a4 in pancreatic ductal cells and AA metabolism in tumor-associated macrophages (TAMs) strongly re-wires the immune landscape by countering tumor acidity and by promoting a pro-inflammatory macrophage switch, respectively. Encouraged by the underlying biology, we are developing molecules targeting the enzymes disclosed by the meta-analysis. The work of this research proposal will consist in the characterization of both molecules in different cancer cell types, tumor types as well as in human co-culture and humanized mouse models. This will enable us to further investigate the clinical potential of those molecules in combination with immune checkpoint blockade. Additionally, a full pharmacological characterization will be carried out to better predict the efficacy of these molecules in cancer patients, which will lead to new therapeutic perspectives for those patients resistant to immunotherapies.