Targeting sphingolipid metabolism to improve anti-melanoma immunotherapy
Immune checkpoint inhibitors (ICI) have shown unprecedented and long-lasting anti-tumor response in patients with metastatic melanoma. To extend the proportion of responders, prevent cancer recurrence and improve the efficacy in other cancers, novel strategies are urgently needed. Also, personalized therapies, based on robust prognostic and predictive factors, are necessary to resource allocation and toxicity management. We recently discovered that sphingolipid (SL) metabolism is strongly altered in melanoma, leading to oncometabolites that modify the tumor microenvironment. Unpublished preclinical data reveal that SLs critically regulate tumor progression and anti-melanoma immune responses. We hypothesize that: (i) SL blocking agents (SBA) synergize with ICI in inducing anti-tumor responses and (ii) SL levels and/or SL-metabolizing enzymes constitute useful biomarkers predictive 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. Moreover, to individualize new immune modulating therapies, IMMUSPHINX aims at identifying prognostic and/or predictive biomarkers. Specifically, IMMUSPHINX will determine: (i) the efficacy of novel approaches combining SBA with ICI; (ii) how SLs affect tumor microenvironment and facilitate anti-melanoma immune responses by analyzing the sphingolipidome of tumors and plasma, and by identifying immune signatures; (iii) whether intratumoral SL metabolizing-enzymes and/or peripheral blood SLs could serve as biomarkers predictive of ICI efficacy. These parameters as well as treatment efficacy in melanoma patients will be analyzed using (Ir) RECIST both in a retrospective and prospective manner. Overall, IMMUSPHINX is an essential step to (i) define the eligibility criteria for this novel strategy combining SBA and ICI, and (ii) set up a clinical trial using SBA as adjuvants for immune-based therapies in cancer patients.
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This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under grant agreement No. 964264.