IMMUSPHINX: Targeting sphingolipid metabolism to improve the efficacy of immunotherapies in melanoma.

Immune checkpoint inhibitors (ICIs) have shown an unprecedented and long-lasting anti-tumour response in patients with metastatic melanoma. To increase the proportion of responders, prevent cancer recurrence and improve efficacy in other cancers, new strategies are urgently needed. In addition, personalised therapies based on robust prognostic and predictive factors are needed for resource allocation and toxicity management.

We have recently discovered that sphingolipid (SL) metabolism is strongly altered in melanoma, leading to oncometabolites that alter the tumour microenvironment. Unpublished preclinical data reveal that SLs critically regulate tumour progression and anti-melanoma immune responses. We hypothesise that: (i) SL blocking agents (SBAs) synergize with ICI in inducing anti-tumor responses and (ii) SL levels and/or SL-metabolising enzymes are useful predictive biomarkers of prognosis and treatment outcome in response to ICI.

IMMUSPHINX aims at developing new combined therapeutic strategies that target both SL metabolism and immune checkpoints.

In addition, to individualise new immunomodulatory therapies, IMMUSPHINX aims at identifying prognostic and/or predictive biomarkers. More specifically, IMMUSPHINX will determine: (i) the efficacy of novel approaches combining SBA and ICI; (ii) how SLs affect the tumour microenvironment and facilitate anti-melanoma immune responses by analysing the sphingolipidome of tumours and plasma, and identifying immune signatures; (iii) whether intratumoral SL metabolizing-enzymes and/or peripheral blood SLs could serve as predictive biomarkers of ICI efficacy. These parameters as well as treatment efficacy in melanoma patients will be analysed using (Ir) RECIST both in a retrospective and prospective manner.

Overall, IMMUSPHINX is an essential step to (i) define the eligibility criteria for this new strategy combining SBA and ICI, and (ii) set up a clinical trial using SBA as an adjuvant for immune therapies in cancer patients.

This programme is coordinated by Nathalie Andrieu-Abadie

For more information:

Start date: 01 April 2017
End date: 30 June 2021

This research programme is part of the European call for proposals ERA-NET TRANSCAN-2 Aligning national/regional translational cancer research programmes and activities

Part of the objectives of this project were published in 2020 and 2021 :

Resistance of melanoma to immune checkpoint inhibitors is overcome by targeting the sphingosine kinase-1.
Imbert C, Montfort A, Fraisse M, Marcheteau E, Gilhodes J, Martin E, Bertrand F, Marcellin M, Burlet-Schiltz O, Peredo AG, Garcia V, Carpentier S, Tartare-Deckert S, Brousset P, Rochaix P, Puisset F, Filleron T, Meyer N, Lamant L, Levade T, Ségui B, Andrieu-Abadie N, Colacios C.
Nat Commun. 2020 Jan 23;11(1):437

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, Junior NF, 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.
Cancer Immunol Res. 2021 May;9(5):568-582.

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