Resistance of Melanoma to Immune Checkpoint Inhibitors is Overcome by Targeting the Sphingosine Kinase 1

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Colacios, Céline | Imbert, Caroline | Montfort, Anne | Fraisse, Marine | Marcheteau, Elie | Gilhodes, Julia | Puisset, F | Filleron, Thomas | Meyer, Nicolas | Lamant, Laurence | Levade, Thierry | Ségui, Bruno | Andrieu-Abadie, Nathalie

Edité par CCSD -

International audience. Immune checkpoint inhibitors (ICI) 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. We observed that high expression of SK1 in tumor cells is associated with shorter survival in melanoma patients treated with anti-PD-1. Interestingly, silencing of SK1 in preclinical models led to attenuated tumor growth and Treg recruitment, and enhanced the CD8/Treg ratio in tumors. Moreover, using epigenetic and pharmacological approaches to target SK1, we show that SK1 expression impairs the responses to ICI in murine models of melanoma, breast and colon cancer. Mechanistically, SK1 silencing decreased the expression of various immunosuppressive factors in the tumor microenvironment to limit regulatory T cell (Treg) infiltration. Accordingly, a SK1-dependent immunosuppressive signature was also observed in human melanoma biopsies. Altogether, this study identifies SK1 as a new checkpoint lipid kinase that could be targeted to enhance immunotherapy.

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