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Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1

Author

Listed:
  • Caroline Imbert

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Anne Montfort

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Marine Fraisse

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Elie Marcheteau

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Julia Gilhodes

    (Institut Universitaire du Cancer Toulouse, Oncopôle
    Institut Claudius Regaud)

  • Elodie Martin

    (Institut Universitaire du Cancer Toulouse, Oncopôle
    Institut Claudius Regaud)

  • Florie Bertrand

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Marlène Marcellin

    (Université Toulouse III—Paul Sabatier
    Institut de Pharmacologie et de Biologie Structurale)

  • Odile Burlet-Schiltz

    (Université Toulouse III—Paul Sabatier
    Institut de Pharmacologie et de Biologie Structurale)

  • Anne Gonzalez de Peredo

    (Université Toulouse III—Paul Sabatier
    Institut de Pharmacologie et de Biologie Structurale)

  • Virginie Garcia

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Stéphane Carpentier

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Sophie Tartare-Deckert

    (Centre Méditerranéen de Médecine Moléculaire, Inserm U1065)

  • Pierre Brousset

    (Cancer Research Center of Toulouse
    Université Toulouse III—Paul Sabatier
    Institut Universitaire du Cancer Toulouse, Oncopôle)

  • Philippe Rochaix

    (Cancer Research Center of Toulouse
    Institut Claudius Regaud)

  • Florent Puisset

    (Cancer Research Center of Toulouse
    Université Toulouse III—Paul Sabatier
    Institut Universitaire du Cancer Toulouse, Oncopôle)

  • Thomas Filleron

    (Institut Universitaire du Cancer Toulouse, Oncopôle
    Institut Claudius Regaud)

  • Nicolas Meyer

    (Cancer Research Center of Toulouse
    Université Toulouse III—Paul Sabatier
    Institut Universitaire du Cancer Toulouse, Oncopôle)

  • Laurence Lamant

    (Cancer Research Center of Toulouse
    Université Toulouse III—Paul Sabatier
    Institut Universitaire du Cancer Toulouse, Oncopôle)

  • Thierry Levade

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier
    Institut Fédératif de Biologie, CHU Purpan)

  • Bruno Ségui

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Nathalie Andrieu-Abadie

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

  • Céline Colacios

    (Cancer Research Center of Toulouse
    Equipe Labellisée Ligue Contre Le Cancer
    Université Toulouse III—Paul Sabatier)

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.

Suggested Citation

  • Caroline Imbert & Anne Montfort & Marine Fraisse & Elie Marcheteau & Julia Gilhodes & Elodie Martin & Florie Bertrand & Marlène Marcellin & Odile Burlet-Schiltz & Anne Gonzalez de Peredo & Virginie Ga, 2020. "Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-019-14218-7
    DOI: 10.1038/s41467-019-14218-7
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