TMIC-13. Modification of the Sphingomyelin-Ceramide balance on the Cell Membrane of Tumor-Associated Myeloid Cells Affects Membrane Permeability

Abstract The poor prognosis of glioblastoma (GBM) mandates novel therapies. Despite the positive results of immunotherapy in many cancers, we have observed disappointing results with immunotherapy for GBM. Metabolic pathways, such as glycolysis, play an important role in tumor development and resistance to chemotherapy. GBM exhibits a metabolic preference toward glycolysis even when oxygen is available. Glycolysis provides a rapid source of ATP and building blocks for cell growth. TAMs, on the other hand, are reprogrammed to a tumor-supporting role and suffer from acidic and hypoxic damage with leaky membrane components, shaped by the glycolytic interaction between TAMs and GBM. This leads to further membrane decomposition in TAMs and loss of capacity for antigen presentation toward T cells. Sphingomyeline constitute a vital class of lipids crucial for maintaining cellular homeostasis and membrane fluidity and are synthesized de novo from serine and palmitate-CoA, with ceramide being the central product generated through a series of enzymatic reactions involving ceramide synthases. Ceramide can be converted to sphingomyelin by sphingomyelin synthase and can be hydrolyzed back to ceramide by acid sphingomyelinase. The ratio between ceramide and sphingomyelin has been shown to play an important role in modulating cell membrane properties, including surface tension, protein accumulation, and membrane protrusions of immune cells as well as cancer cells. Our study reveals that treatment with small-molecule drugs, LCL521, not only prevents TAM exhaustion but also shunts TAMs away from glycolytic damage as observed by increased sphingomyelin, membrane protrusions, and cell-cell communication.