1. Data from Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti–PD-1 Therapy Efficacy
- Author
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Bruno Ségui, Céline Colacios, Olivier Micheau, Nicolas Meyer, Hervé Benoist, Yusuf A. Hannun, Thierry Levade, Nathalie Andrieu-Abadie, Nicole Therville, Sandrine Silvente-Poirot, Philippe Rochaix, Pierre Brousset, Pierre Cordelier, Michel Record, Virginie Garcia, Nilton De França Junior, Andrei A. Constantinescu, Florent Dufour, Christopher J. Clarke, Marie Tosolini, Joëlle Riond, Caroline Imbert, Carine Dufau, Jean Milhès, Thomas Filleron, Julia Gilhodes, Julia Rochotte, Florie Bertrand, and Anne Montfort
- Abstract
Dysregulation of lipid metabolism affects the behavior of cancer cells, but how this happens is not completely understood. Neutral sphingomyelinase 2 (nSMase2), encoded by SMPD3, catalyzes the breakdown of sphingomyelin to produce the anti-oncometabolite ceramide. We found that this enzyme was often downregulated in human metastatic melanoma, likely contributing to immune escape. Overexpression of nSMase2 in mouse melanoma reduced tumor growth in syngeneic wild-type but not CD8-deficient mice. In wild-type mice, nSMase2-overexpressing tumors showed accumulation of both ceramide and CD8+ tumor-infiltrating lymphocytes, and this was associated with increased level of transcripts encoding IFNγ and CXCL9. Overexpressing the catalytically inactive nSMase2 failed to alter tumor growth, indicating that the deleterious effect nSMase2 has on melanoma growth depends on its enzymatic activity. In vitro, small extracellular vesicles from melanoma cells overexpressing wild-type nSMase2 augmented the expression of IL12, CXCL9, and CCL19 by bone marrow–derived dendritic cells, suggesting that melanoma nSMase2 triggers T helper 1 (Th1) polarization in the earliest stages of the immune response. Most importantly, overexpression of wild-type nSMase2 increased anti–PD-1 efficacy in murine models of melanoma and breast cancer, and this was associated with an enhanced Th1 response. Therefore, increasing SMPD3 expression in melanoma may serve as an original therapeutic strategy to potentiate Th1 polarization and CD8+ T-cell–dependent immune responses and overcome resistance to anti–PD-1.
- Published
- 2023
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