Glioblastoma-enriched glycosphingolipids modulate the function of human iNKT cells

To develop effective therapies for glioblastoma (GBM), a deeper understanding of its underlying immunoregulatory mechanisms is needed. Invariant natural killer T (iNKT) cells are unconventional T cells that recognize lipid antigens and are known to regulate tumor immunity in other cancer types. Given the lipid-rich nature of the brain and the unique metabolic activity of GBM cells, we hypothesized that GBM-enriched lipids could direct iNKT cells to contribute to the immunosuppressive nature of the disease. Lipid levels of multiple human GBM stem-like cell (GSC) lines, low grade-glioma lines, and normal human astrocytes were determined using LC/MS. GSC-enriched lipids were tested in iNKT stimulation assays, with either human iNKT cell lines or PBMC samples from both healthy donors and GBM patients, to determine antigenicity and characterize the nature of iNKT activation. Multiple lipid species were found to be uniquely enriched in GSCs. Many of these lipids, called sulfatides, were recognized by and activated iNKT cells in a dose-dependent manner when presented by CD1d. Pharmaceutical and genetic targeting of the sulfatide synthetic pathway within GSCs resulted in an altered ability to activate iNKT cells. However, one lipid, lyso-sulfatide, inhibited the activation of iNKT cells and suppressed activation induced by a cognate antigen, a-galactosylceramide. The modulation of iNKT cell functions by GSC-enriched glycosphingolipids may contribute to the immunosuppression of GBM and highlights sulfatide production as a potential therapeutic target for GBM treatment. Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2025. This work is written by (a) US Government employee(s) and is in the public domain in the US.

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