Interconnections between TNF signalling and ceramide metabolism in melanoma

Pr Bruno Ségui
Associate Investigators : Drs Nathalie Andrieu, Céline Colacios, Anne Montfort

Our recent work has demonstrated the importance of TNF in the inhibition of CD8+ T cell-dependent anti-tumour responses and resistance to anti-PD-1 in melanoma. TNF also contributes to immune evasion by triggering activation-induced cell death in T cells, immunosuppressive cells infiltration in tumours, dedifferentiation of melanoma cells (loss of MITF and melanocyte antigen expression, EMT-like process) and expression of immunosuppressive molecules such as PD-L1 and TIM-3. As TNF is a key modulator of ceramide metabolism, we hypothesise that alterations in ceramide metabolism may contribute to TNF-dependent mechanisms of ICI resistance. We are investigating the impact of TNF on ceramide metabolism in melanoma cells and immune cells. We are assessing how ceramide-dependent metabolic pathways affect immune escape from melanoma in response to TNF. We are also studying how ceramide metabolism in immune cells alters their phenotype, including their effector and immunosuppressive functions.

Funding:

Association pour la Recherche sur le Cancer; Fondation Toulouse Cancer Santé

Illustration :

Infiltration accrue des lymphocytes T CD8 dans des tumeurs issues de souris déficientes en TNF (Extrait de Bertrand et al., Cancer Res. 2015) / Increased infiltration of CD8 T cells in tumours from TNF-deficient mice (from Bertrand et al., Cancer Res. 2015)