CD95L/FasL, belongs to the TNF superfamily. This transmembrane ligand can be cleaved by metalloproteases to release a soluble s-CD95L (soluble CD95L).
While the interaction of the membrane-bound CD95L (m-CD95L) to its receptor CD95 (also known as Fas) induces an apoptotic signal leading to cell death, its soluble counterpart fails to do it and triggers non-apoptotic signaling pathways (i.e., PI3K, NFkB).
We observed that s-CD95L can promote inflammation in lupus patients1 and metastatic dissemination in triple negative breast cancer (TNBC) women 2. More recently, we found that the loss of CD95 in TNBC cells engenders a natural killer cell (NK)-mediated anti-tumor response 3. Interestingly, CD95 elimination in TNBC cells implements an inflammatory transcriptomic signature by activating the NFkB signaling pathway 4 that could account for this anti-tumor response.
These recent findings suggest that although CD95 expression in TNBC cells could favor the elimination of tumor cells by CD95L-expressing immune cells (i.e., activated T cells), its loss induces an NFkB response that might account for a NK-mediated anti-tumor response.
The pro-inflammatory mechanism induced by s-CD95L accumulation and CD95 loss will be discuss in this presentation.
Patrick Legembre is an immunologist with strong interest in cell signalling, working on the role of the death receptor signalling in human diseases. He defended his PhD at University of Bordeaux in 2002 on the apoptotic roles of the death receptor CD95, then moved to University of Chicago between 2002 and 2005 to decipher how the same receptor could favour metastatic dissemination of cancer cells.
As a principal researcher in France (Inserm) in 2005, he created a group studying how the non-apoptotic signals of CD95 contribute to i) aggravate chronic inflammatory disorders including chronic lupus erythematosus and ii) promote the metastatic dissemination of cancers such as triple negative breast cancers. In collaboration with chemists and modelers, he developed some Medicinal chemistry programs to develop drugs selectively targeting the CD95-mediated non apoptotic signals and validated their therapeutic values in different animal models. He is now working at University of Limoges.
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