Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1
Caroline Imbert, Anne Montfort, Marine Fraisse, Elie Marcheteau, Julia Gilhodes, Elodie Martin, Florie Bertrand, Marlène Marcellin, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Virginie Garcia, Stéphane Carpentier, Sophie Tartare-Deckert, Pierre Brousset, Philippe Rochaix, Florent Puisset, Thomas Filleron, Nicolas Meyer, Laurence Lamant, Thierry Levade, Bruno Ségui, Nathalie Andrieu-Abadie, Céline Colacios, Caroline Imbert, Anne Montfort, Marine Fraisse, Elie Marcheteau, Julia Gilhodes, Elodie Martin, Florie Bertrand, Marlène Marcellin, Odile Burlet-Schiltz, Anne Gonzalez de Peredo, Virginie Garcia, Stéphane Carpentier, Sophie Tartare-Deckert, Pierre Brousset, Philippe Rochaix, Florent Puisset, Thomas Filleron, Nicolas Meyer, Laurence Lamant, Thierry Levade, Bruno Ségui, Nathalie Andrieu-Abadie, Céline Colacios
Abstract
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.
Conflict of interest statement
N.M. has worked as an investigator and/or consultant and/or speaker for BMS, MSD, Amgen, Roche, GSK, Novartis, Pierre Fabre. B.S. has worked as an investigator, consultant and speaker for BMS. The authors declare that they have no other conflict of interest.
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References
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