Modulation of Acid Sphingomyelinase in Melanoma Reprogrammes the Tumour Immune Microenvironment

Abstract

The inflammatory microenvironment induces tumours to acquire an aggressive and immunosuppressive behaviour. Since acid sphingomyelinase (A-SMase) downregulation in melanoma was shown to determine a malignant phenotype, we aimed here to elucidate the role of A-SMase in the regulation of tumour immunogenic microenvironment using in vivo melanoma models in which A-SMase was either downregulated or maintained at constitutively high levels. We found high levels of inflammatory factors in low A-SMase expressing tumours, which also displayed an immunosuppressive/protumoural microenvironment: high levels of myeloid-derived suppressor cells (MDSCs) and regulatory T lymphocytes (Tregs), as well as low levels of dendritic cells (DCs). In contrast, the restoration of A-SMase in melanoma cells not only reduced tumour growth and immunosuppression, but also induced a high recruitment at tumour site of effector immune cells with an antitumoural function. Indeed, we observed a poor homing of MDSCs and Tregs and the increased recruitment of CD8+ and CD4+ T lymphocytes as well as the infiltration of DCs and CD8+/CD44high T lymphocytes. This study demonstrates that change of A-SMase expression in cancer cells is sufficient per se to tune in vivo melanoma growth and that A-SMase levels modulate immune cells at tumour site. This may be taken into consideration in the setting of therapeutic strategies.

Acid Sphingomyelinase (ASM) is a Negative Regulator of Regulatory T Cell (Treg) Development

“…Sphingolipids participate in the pathophysiology of cancer, neurodegeneration, neuroinflammation as well as autoimmune disorders [21,24,27,28]. However, how ASM is involved in the development of Treg had not been defined.…”

“…Deficiency of this enzyme leads to Niemann-Pick disease (NPD) in humans [22,23]. Deregulated ASM function is involved in many pathologies including; inflammation and infection, cystic fibrosis, Wilson disease, type 2 diabetes, cardiovascular disease, cerebral ischemia, autoimmune multiple sclerosis, major depression, Parkinson disease, and Alzheimer's disease [19,21,[23][24][25][26][27][28]. In platelets, ASM regulates cell membrane scrambling, secretion and thrombus formation [29].…”

Drp1 overexpression induces desmin disassembling and drives kinesin-1 activation promoting mitochondrial trafficking in skeletal muscle

“…RT-qPCR was performed using the g SsoAdvanced Universal SYBR Green Supermix (Bio-Rad) and the CFX96 Touch Real-Time PCR Detection System (Bio-Rad). All reactions were run as triplicates and the fold changes determined relative to the 36B4 housekeeping transcripts using the 2 −ΔΔCT formula [25].…”

Essential role for acid sphingomyelinase-inhibited autophagy in melanoma response to cisplatin

“…We recently found that A-SMase actually contributes to determine the malignant phenotype of melanoma cells in vitro and in vivo in terms of tumour progression, invasiveness and metastatic capacity. In addition, A-SMase levels of expression correlated with melanoma grade in human biopsies [ 37 , 38 ]. Tumours expressing low A-SMase levels displayed high levels of inflammatory factors and an immune-suppressive/pro-tumoural microenvironment.…”

“…Tumours expressing low A-SMase levels displayed high levels of inflammatory factors and an immune-suppressive/pro-tumoural microenvironment. Overexpression of A-SMase induced a high recruitment at the tumour site of effector immune cells with an anti-tumoural function [ 37 , 38 ]. Interestingly A-SMase and sphingolipids appear to regulate autophagy, especially the process of lysosome trafficking and fusion [ 39 , 40 ].…”