Reprogramming a family of lipids to increase the effectiveness of melanoma immunotherapy.

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

This work contributes to the scientific rationale of IMMUSPHINX (NCT03627026), a clinical trial 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 tumour biopsies and blood samples. This trial, promoted by the Claudius Regaud Institute, started in January 2019 and is funded in the framework of a European project (ERA-NET Transcan-2 H2020).

This work is the subject of a patent: WO2017134116A1: Processes and pharmaceutical compositions to amplify CD8+ T cell dependent immune responses in cancer patients.

Collaborations and acknowledgements

INSERM, Toulouse III- Paul Sabatier University, Ligue Nationale Contre le Cancer (LNCC, Equipe Labellisée 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, Toulouse Cancer laboratory of excellence (LABEX TOUCAN)

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