Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.
Caroline ImbertAnne MontfortMarine FraisseElie MarcheteauJulia GilhodesElodie MartinFlorie BertrandMarlène MarcellinOdile Burlet-SchiltzAnne Gonzalez de PeredoVirginie GarciaStéphane CarpentierSophie Tartare-DeckertPierre BroussetPhilippe RochaixFlorent PuissetThomas FilleronNicolas MeyerLaurence LamantThierry LevadeBruno SéguiNathalie Andrieu-AbadieCéline ColaciosPublished in: Nature communications (2020)
Immune checkpoint inhibitors (ICIs) have dramatically modified the prognosis of several advanced cancers, however many patients still do not respond to treatment. Optimal results might be obtained by targeting cancer cell metabolism to modulate the immunosuppressive tumor microenvironment. Here, we identify sphingosine kinase-1 (SK1) as a key regulator of anti-tumor immunity. Increased expression of SK1 in tumor cells is significantly associated with shorter survival in metastatic melanoma patients treated with anti-PD-1. Targeting SK1 markedly enhances the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreases the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature is also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a checkpoint lipid kinase that could be targeted to enhance immunotherapy.
Keyphrases
- poor prognosis
- end stage renal disease
- protein kinase
- chronic kidney disease
- transcription factor
- endothelial cells
- newly diagnosed
- cancer therapy
- tyrosine kinase
- ejection fraction
- skin cancer
- binding protein
- dna damage
- cell cycle
- prognostic factors
- gene expression
- young adults
- cell proliferation
- patient reported outcomes