Immunotherapy for advanced melanoma has revolutionized the treatment of this deadly cancer. However, almost half of patients do not respond to this treatment and die within 5 years after starting treatment. Our work shows that melanoma cells exhibit alterations in the metabolism of a family of lipids, the sphingolipids, which contribute to resistance to immunotherapies. We propose an original strategy to reprogram this metabolism by expressing in melanoma cells an enzyme, neutral sphingomyelinase 2, which stimulates the immune response against cancer cells and sensitizes them to immunotherapies in preclinical models of melanoma. In patients with advanced melanoma, expression of this enzyme in tumor biopsies is associated with a good prognosis.

This work contributes to the scientific rationale of IMMUSPHINX (NCT03627026), a clinical trial conducted in 60 patients with advanced melanoma treated with immunotherapy (nivolumab with or without ipilimumab; pembrolizumab). The primary objective of IMMUSPHINX is to predict patient response to immunotherapies by establishing signatures of sphingolipid metabolism from tumor and blood samples. This trial, promoted by the Claudius Regaud Institute, started in January 2019 and is funded as part of a European project (ERA-NET Transcan-2 H2020).

this work is the subject of a patent : WO2017134116A1 : Methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer.

Discover the published article :

Cancer Immunol Res. 2021 Mar 16:canimm.0342.2020. doi: 10.1158/2326-6066.CIR-20-0342. Online ahead of print.
Neutral sphingomyelinase 2 heightens anti-melanoma immune responses and anti-PD-1 therapy efficacy.
Montfort A, Bertrand F, Rochotte J, Gilhodes J, Filleron T, Milhès J, Dufau C, Imbert C, Riond J, Tosolini M, Clarke CJ, Dufour F, Constantinescu AA, de França Junior N, Garcia V, Record M, Cordelier P, Brousset P, Rochaix P, Silvente-Poirot S, Therville N, Andrieu-Abadie N, Levade T, Hannun YA, Benoist H, Meyer N, Micheau O, Colacios C, Ségui B.

Key words :

  • Ceramide,
  • metabolism,
  • anti-PD-1,
  • anti-CTLA-4,
  • melanoma immunotherapy,
  • melanoma resistance

Collaborations and thanks

We thank INSERM, Université Toulouse III- Paul Sabatier, Ligue Nationale Contre le Cancer (LNCC, Equipe Labellis#ee 2013), Ligue Régionale Contre le Cancer (Midi-Pyrénées), INSERM Transfert, Cancéropôle Grand Sud-Ouest, ROTARY Toulouse clubs, Fondation Toulouse Cancer Santé, Fondation ARC (Equipe Labellisée 2019), Transcan-2 Research Program (ERA-NET Transcan-2), Marie Curie Actions, Fondation de France, laboratoire d’excellence Toulouse Cancer (LABEX TOUCAN)

Contact :

Bruno Ségui & Céline Colacios
Equipe du CRCT : Ceramide metabolism in melanoma
Mail : bruno.segui@inserm.fr ; celine.colacios@inserm.fr

One Picture

Melanoma cells weakly express neutral sphingomyelinase 2. Expression of neutral sphingomyelinase 2 (in red) is assessed by in situ hybridization (RNA Scope) in tumor biopsies from patients with advanced melanoma. Blue box: healthy epidermis and dermis; red inset: area of dermis rich in melanoma cells.