Shikhar Mehrotra

Mechanisms of SK1/S1P signaling in regulating T cell immunotherapy.

Long-term Objective: Cancer therapies based on stimulating the patient's immune system represent an important treatment modality, but much remains to be discovered to optimize their use. One key-confounding factor that hampers the adoptive T cell therapy is the issue of T cell homing to the tumors and their persistence in immunosuppressive tumor microenvironment. Given the unexplored role of sphingolipid metabolism in regulating peripheral T cell response, we believe that the studies proposed herein will help identify the role of sphingosine-1phosphate/sphingosine-1 phosphate receptor signaling and energy metabolism in T cell subsets - with the overall goal to improve adoptive T cell transfer therapy for cancer.  Relevance to Lipid pathobiology: The role lipids in tumor progression are well established. Although, how lipids affect the immune cell functions is not well established. While a few recent studies have shown the role of lipids in regulating suppressive regulatory T cells or dendritic cells, the specific role of sphingosine kinase isoforms remains unexplored. This proposal aims to address the mechanisms that lead to enhanced tumor control when using T cells deficient in sphingosine kinase-1.

Translational potential and clinical impact: We plan to use the specific Sphingosine kinase-1 inhibitor to treat the wild type T cells and determine if we can mimic the enhanced tumor control that was observed when using the SphK1-/- T cells. We believe that while the confirmatory mechanistic experiments will require the T cell specific deletion of SphK, the use of pharmacological agents to enhance T cell potential to control tumor growth will be of immediate translational significance.