Defining the role of sphingolipid synthesis in anti-tumor immunity

About This Grant

PROJECT SUMMARY Cancer cells require substantial rewiring of lipid metabolic events due to high demands to generate new cellular membranes. Recent evidence suggests that changes in lipid metabolism enable cancer cells to survive under nutrient- and oxygen-deprived environments and facilitate evasion from attack by immune cells. These responses are partly due to alterations in the lipid composition of the tumor microenvironment (TME), which modulates immune cell functions. A vital issue to consider is that organismal metabolism impacts the TME, and we hypothesize that dietary lipid intake can be leveraged to regulate essential functions of TME cellular components to treat diverse types of cancer. Previous work identified correlations between tumor lipid homeostasis and immune evasion; however, the molecular pathways involved in this process have not been identified. Moreover, it is unclear which dietary lipids, if any, impact tumor growth and anti-tumor immunity. In preliminary studies, we performed in vivo genetic screens in a Kras-mutant mouse models of pancreatic and colorectal cancers and compared metabolic dependencies of cancer cells growing in immunocompetent mice to those of mice lacking most mature immune cells. We identified sphingolipid synthesis catalyzed by serine palmitoyl transferase (SPT) as the major metabolic requirement for tumor growth. Loss of sphingolipid synthesis substantially decreased tumor growth, but only in the presence of an intact immune system. Furthermore, decreasing sphingolipid levels through genetic and pharmacologic means sensitized cancer cells to natural killer (NK)- and T cell-mediated killing. This study will expand these observations by testing the hypothesis that sphingolipid availability in tumors mediates immune evasion. In addition, we will assess the effect of dietary fats on tumor growth. We will first test the therapeutic potential of sphingolipid synthesis inhibition alone and in combination with checkpoint inhibitors. Using a combination of hypothesis-driven unbiased approaches, we will then identify the mechanism by which sphingolipids mediate immune cell evasion. Lastly, we will use dietary studies to change tumor sphingolipid availability and test their potential to impact tumor immune evasion and responses to immunotherapy. Animal use is scientifically justified as essential to address the study aims, as no alternative models can currently be used to evaluate the role of lipid metabolism in regulating anti-tumor immunity in tumor microenvironment. Using clinically-relevant mouse models of cancer, we aim to study the interactions among tumor cells, diet, and the immune system, in a living whole organism. Proposed animal studies will adhere to the principles of reduction, refinement, and replacement. Our work will advance our understanding of a previously unappreciated link between tumor sphingolipids and tumor immunity. The results have a high potential to identify new strategies to manage difficult-to-treat and immune evasive tumors.