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Neutral Sphingomyelinase 2 Heightens Anti-Melanoma Immune Responses and Anti–PD-1 Therapy Efficacy

免疫系统 黑色素瘤 癌症研究 医学 免疫疗法 PD-L1 免疫学
作者
Anne Montfort,Florie Bertrand,Julia Rochotte,Julia Gilhodes,Thomas Filleron,Jean Milhès,Carine Dufau,Caroline Imbert,Joëlle Riond,Marie Tosolini,Christopher J. Clarke,Florent Dufour,Andrei Constantinescu,Nilton De França,Virginie Garcia,Michel Record,Pierre Cordelier,Pierre Brousset,Philippe Rochaix,Sandrine Silvente‐Poirot,Nicole Therville,Nathalie Andrieu‐Abadie,Thierry Levade,Yusuf A. Hannun,Hervé Benoist,Nicolás Meyer,Olivier Micheau,Céline Colacios,Bruno Ségui
出处
期刊:Cancer immunology research [American Association for Cancer Research]
卷期号:9 (5): 568-582 被引量:40
标识
DOI:10.1158/2326-6066.cir-20-0342
摘要

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.
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