Abstract: Advanced cutaneous melanoma can be treated by immunotherapy targeting immune check points such as PD-1 and CTL-A4. However, 50% of patients do no respond because of primary or acquired resistance mechanism. Thus, new targets for addressing the treatment of said resistance are highly needed. The inventors show that TNF (Tumour Necrosis Factor) and ceramide metabolism alterations in melanoma cells contribute to melanoma progression and resistance to immunotherapies. In particular, the inventors demonstrate that TNF is a potent modulator of ceramide metabolism and TNF-mediated ceramide metabolism changes contribute to various biological processes such as cell proliferation, cell death and cell differentiation. Among the biological processes by which TNF triggers melanoma immune escape and resistance to immunotherapies, TNF triggers a dedifferentiation process of melanoma cells associated with the reduction of melanocytic antigen expression and epithelial to mesenchy mal transition.

Abstract: The present invention relates to methods and pharmaceutical composition for the treatment of cancer. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: administering a pharmaceutically effective amount of a TNF? blocking agent to a subject in combination with the immune checkpoint inhibitor.

Abstract: Immune checkpoint blockade therapy is based on the inhibition of the tumor-mediated suppression of anticancer immune responses. However, the efficacy and effectiveness of said therapy vary greatly across individual patients and among different tumor types. A substantial unmet need is thus to identify novel targets that can enhance the therapeutic efficacy of the immune checkpoint blockade therapy. S1P is produced by sphingosine kinases (i.e. SK1 and SK2) that catalyze the phosphorylation of sphingosine to SIP. SK2 inhibitors were described as suitable for the treatment of cancer. However the role of SK2 in the immune tumor microenvironment has never been investigated. The inventors now showed that genetic deletion of SPHK2 leads to a delay in the melanoma tumor growth and an increase in tumor-infiltrating effector lymphocytes. In particular the increase of tumor-infiltrating effector lymphocytes in the tumor is associated with a decrease in the amount of tumor-infiltrating myeloid-derived suppressor cells.

Abstract: The present invention relates to methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer. In particular, the present invention relates to a method of enhancing the CD8+ T cell-dependent immune response in a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of an agent capable of increasing intra-tumoral ceramide content.

Abstract: The present invention relates to methods and pharmaceutical composition for the treatment of cancer. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: administering a pharmaceutically effective amount of a TNF? blocking agent to a subject in combination with the immune checkpoint inhibitor.

Abstract: Immune checkpoint inhibitors (ICI) have revolutionized therapy for advanced cancer, however many patients still do not respond to treatment. However, the efficacy and effectiveness of these therapies varies greatly across individual patients and among different tumour types. A substantial unmet need is thus the development of biomarkers of response to ICI, in order to identify, before initiation of treatment, which patients are likely to experience a response to and clinical benefit from such treatments. Here, the inventors analyzed SPHK1 mRNA in tumor biopsies by in situ hybridization using the RNAscope technology in a cohort of 32 patients suffering from metastatic melanoma. They showed that elevated expression of SPHK1, encoding sphingosine kinase 1 (SK1), which produces the oncometabolite sphingosine-1-phosphate (S1P) is associated with a poor survival in metastatic melanoma patients treated with to the well-known immune-checkpoint inhibitor anti-PD-1 antibody.

Abstract: The present invention relates to methods and pharmaceutical composition for the treatment of cancer. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: administering a pharmaceutically effective amount of a TNF? blocking agent to a subject in combination with the immune checkpoint inhibitor.

Abstract: The present invention relates to methods for enhancing the potency of the immune checkpoint inhibitors. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering a pharmaceutically effective amount of a SK1 inhibitor to a subject in combination with the immune checkpoint inhibitor.

Abstract: The present invention relates to methods for enhancing the potency of the immune checkpoint inhibitors. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering a pharmaceutically effective amount of a SK1 inhibitor to a subject in combination with the immune checkpoint inhibitor.

Abstract: The present invention relates to methods and pharmaceutical composition for the treatment of cancer. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen for cancer, the method comprising: administering a pharmaceutically effective amount of a TNF? blocking agent to a subject in combination with the immune checkpoint inhibitor.

Abstract: The present invention relates to methods and pharmaceutical compositions for enhancing CD8+ T cell-dependent immune responses in subjects suffering from cancer. In particular, the present invention relates to a method of enhancing the CD8+ T cell-dependent immune response in a subject suffering from cancer comprising administering to the subject a therapeutically effective amount of an agent capable of increasing intra-tumoral ceramide content.

Abstract: The present invention relates to methods for enhancing the potency of the immune checkpoint inhibitors. In particular, the present invention relates to a method for enhancing the potency of an immune checkpoint inhibitor administered to a subject as part of a treatment regimen, the method comprising administering a pharmaceutically effective amount of a SK1 inhibitor to a subject in combination with the immune checkpoint inhibitor.

Abstract: The present invention relates to a TNF? blocking agent for use in the treatment and prevention of melanoma in a subject in whom melanoma cells express MHCI and in whom stroma cells exhibit TNF expression.

Abstract: The present invention relates to methods and pharmaceutical compositions for preventing or reducing metastatic dissemination (i.e. reducing motility of cancer cells). In particular, the present invention relates to a method for preventing or reducing metastatic dissemination (i.e. reducing motility of cancer cells) in a subject suffering from a cancer comprising the steps consisting of i) determining the expression level of at least one biomarker selected from the group consisting of soluble CD95L and EMT promoting factors in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering the subject with a therapeutically effective amount of C16-ceramide or derivatives such as C16-sphingomyelin and C16-glycosphingolipids when the expression level determined at step i) is higher than the predetermined reference value.

Abstract: The present invention relates to a TNF? blocking agent for use in the treatment and prevention of melanoma in a subject in whom melanoma cells express MHCI and in whom stroma cells exhibit TNF expression.

Abstract: The present invention relates to methods and pharmaceutical compositions for preventing or reducing metastatic dissemination (i.e. reducing motility of cancer cells). In particular, the present invention relates to a method for preventing or reducing metastatic dissemination (i.e. reducing motility of cancer cells) in a subject suffering from a cancer comprising the steps consisting of i) determining the expression level of at least one biomarker selected from the group consisting of soluble CD95L and EMT promoting factors in a sample obtained from the subject, ii) comparing the expression level determined at step i) with a predetermined reference value and iii) administering the subject with a therapeutically effective amount of C16-ceramide or derivatives such as C16-sphingomyelin and C16-glycosphingolipids when the expression level determined at step i) is higher than the predetermined reference value.