CD95/Fas, Non-Apoptotic Signaling Pathways, and Kinases.

Matthieu Le Gallo,Patrick Blanco,Amanda Poissonnier,Patrick Legembre

doi:10.3389/fimmu.2017.01216

Abstract

Endothelial cells lining new blood vessels that develop during inflammatory disorders or cancers act as doors that either allow or block access to the tumor or inflamed organ. Recent data show that these endothelial cells in cancer tissues and inflamed tissues of lupus patients overexpress CD95L, the biological role of which is a subject of debate. The receptor CD95 (also named Fas or apoptosis antigen 1) belongs to the tumor necrosis factor (TNF) receptor superfamily. Its cognate ligand, CD95L, is implicated in immune homeostasis and immune surveillance. Because mutations of this receptor or its ligand lead to autoimmune disorders such as systemic lupus erythematosus (SLE) and cancers, CD95 and CD95L were initially thought to play a role in immune homeostasis and tumor elimination via apoptotic signaling pathways. However, recent data reveal that CD95 also evokes non-apoptotic signals, promotes inflammation, and contributes to carcinogenesis; therefore, it is difficult to dissect its apoptotic effects from its non-apoptotic effects during pathogenesis of disease. CD95L is cleaved by metalloproteases and so exists in two different forms: a transmembrane form and a soluble ligand (s-CD95L). We recently observed that the soluble ligand is overexpressed in serum from patients with triple-negative breast cancer or SLE, in whom it contributes to disease severity by activating non-apoptotic signaling pathways and promoting either metastatic dissemination or accumulation of certain T cell subsets in damaged organs. Here, we discuss the roles of CD95 in modulating immune functions via induction of mainly non-apoptotic signaling pathways.

Highlights

Accumulating evidence suggests that high endothelial venule (HEV) density in the tumor stroma is a strong predictor of infiltration by CD4+ T, CD8+ T, and B cells
In an effort to explain the CD95-driven accumulation of Th17 cells in damaged organs, we showed that these Th17 cells exposed to s-CD95L upregulate expression of the adhesion molecule PSGL-1, which promotes tethering of lymphocytes to endothelial cells and subsequent rolling (Figure 1) and provokes secretion of effector cytokines when highly expressed by T cells [66]
The role of endothelial CD95L remains controversial because, while Coukos et al observed that the membrane-bound ligand served as a barrier to prevent CD8 T-cell extravasation [53] (Figure 1), we found that CD95L on the surface of endothelial cells can be cleaved by metalloproteases to create a gradient that is responsible for accumulation of Th17 cells in inflamed organs [10, 36] or the metastatic dissemination of triple-negative breast cancer (TNBC) cells [37] (Figure 1)

Summary

Introduction

Accumulating evidence suggests that high endothelial venule (HEV) density in the tumor stroma is a strong predictor of infiltration by CD4+ T, CD8+ T, and B cells. Novel studies revisited the biological role of CD95 and found that this receptor activates non-apoptotic signaling pathways, FIGURE 1 | CD95L is a chemoattractant for inflammatory T cells and triple-negative breast cancer (TNBC) cells.

Results

Conclusion