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Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer
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Journal Article
Glycosphingolipid synthesis mediates immune evasion in KRAS-driven cancer
2024
Overview
Cancer cells frequently alter their lipids to grow and adapt to their environment
1
–
3
. Despite the critical functions of lipid metabolism in membrane physiology, signalling and energy production, how specific lipids contribute to tumorigenesis remains incompletely understood. Here, using functional genomics and lipidomic approaches, we identified de novo sphingolipid synthesis as an essential pathway for cancer immune evasion. Synthesis of sphingolipids is surprisingly dispensable for cancer cell proliferation in culture or in immunodeficient mice but required for tumour growth in multiple syngeneic models. Blocking sphingolipid production in cancer cells enhances the anti-proliferative effects of natural killer and CD8
+
T cells partly via interferon-γ (IFNγ) signalling. Mechanistically, depletion of glycosphingolipids increases surface levels of IFNγ receptor subunit 1 (IFNGR1), which mediates IFNγ-induced growth arrest and pro-inflammatory signalling. Finally, pharmacological inhibition of glycosphingolipid synthesis synergizes with checkpoint blockade therapy to enhance anti-tumour immune response. Altogether, our work identifies glycosphingolipids as necessary and limiting metabolites for cancer immune evasion.
Functional genomics and lipidomic analyses reveal that sphingolipid synthesis is required for tumour immune evasion and tumour growth in vivo, mediated in part by the impact of glycosphingolipid synthesis on cell surface expression of IFNγ receptors.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 13/109
/ 13/31
/ 14/34
/ 38/91
/ 45
/ 45/41
/ Animals
/ Cancer
/ CD8-Positive T-Lymphocytes - immunology
/ Enzymes
/ Female
/ Genes
/ Genomics
/ Glycosphingolipids - biosynthesis
/ Glycosphingolipids - deficiency
/ Glycosphingolipids - immunology
/ Glycosphingolipids - metabolism
/ Humanities and Social Sciences
/ Immune checkpoint inhibitors
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Interferon gamma Receptor - metabolism
/ Interferon-gamma - immunology
/ Killer Cells, Natural - immunology
/ Lipids
/ Mice
/ Proto-Oncogene Proteins p21(ras) - metabolism
/ Science
/ Tumors
