0 avis
Neutral sphingomyelinase 2 heightens anti-melanoma immune response and synergizes with immune checkpoint inhibitors.
Archive ouverte
Edité par CCSD -
International audience. As part of a network of enzymes modulating the generation and degradation of sphingolipids, neutral sphingomyelinase 2 (nSMase2) catalyses the hydrolysis of the plasma membrane sphingomyelin into ceramide. In cancer, this bioactive lipid is considered as an anti-oncometabolite. Gene expression analyses from the melanoma TCGA database revealed that SMPD3, the gene coding for nSMase2, was expressed at lower levels in tumours from metastatic melanoma patients as compared to patients depicting only primary masses. Moreover, high levels of the SMPD3 transcript in metastases were associated with better overall survival for patients. In the mouse B16 melanoma model, which displays low levels of nSMase2, overexpression of this enzyme did not affect cell growth under 2D or 3D culture conditions, however it decreased tumour growth in vivo. In the settings, nSMase2 overexpression increased the infiltration of tumours by CD8+ T cells and the nSMase2-dependent delayed tumour growth was abolished in CD8 KO mice. This depended on nSMase2 enzymatic activity as overexpression of a catalytically inactive form of nSMase2 did not impede tumour growth. Mechanistically, increased nSMase2 activity prompted melanoma cells to release small extracellular vesicles enriched for the immunogenic miR155, thus favouring dendritic cell activation as well as CD8 infiltration in vivo. Finally, increased nSMase2 activity in tumours synergized with anti-PD-1 therapy to abolish melanoma growth in vivo. Overall, our work highlights how the tumour-intrinsic sphingomyelin metabolism can shape the immune microenvironment of melanoma.
Consulter en ligne
Suggestions
Du même auteur
