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 and Céline Colacios ()
Additional contact information
Caroline Imbert: Cancer Research Center of Toulouse
Anne Montfort: Cancer Research Center of Toulouse
Marine Fraisse: Cancer Research Center of Toulouse
Elie Marcheteau: Cancer Research Center of Toulouse
Julia Gilhodes: Institut Universitaire du Cancer Toulouse, Oncopôle
Elodie Martin: Institut Universitaire du Cancer Toulouse, Oncopôle
Florie Bertrand: Cancer Research Center of Toulouse
Marlène Marcellin: Université Toulouse III—Paul Sabatier
Odile Burlet-Schiltz: Université Toulouse III—Paul Sabatier
Anne Gonzalez de Peredo: Université Toulouse III—Paul Sabatier
Virginie Garcia: Cancer Research Center of Toulouse
Stéphane Carpentier: Cancer Research Center of Toulouse
Sophie Tartare-Deckert: Centre Méditerranéen de Médecine Moléculaire, Inserm U1065
Pierre Brousset: Cancer Research Center of Toulouse
Philippe Rochaix: Cancer Research Center of Toulouse
Florent Puisset: Cancer Research Center of Toulouse
Thomas Filleron: Institut Universitaire du Cancer Toulouse, Oncopôle
Nicolas Meyer: Cancer Research Center of Toulouse
Laurence Lamant: Cancer Research Center of Toulouse
Thierry Levade: Cancer Research Center of Toulouse
Bruno Ségui: Cancer Research Center of Toulouse
Nathalie Andrieu-Abadie: Cancer Research Center of Toulouse
Céline Colacios: Cancer Research Center of Toulouse

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-019-14218-7

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