Different ways for CD95/Fas to induce inflammation in chronic inflammatory disorders and cancers

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.