Endophilin A3-mediated clathrin-independent endocytosis and retrograde transport in cancer cells promote cytotoxic CD8 T cell activation
(2025)
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- Abstract
- Endocytosis, a fundamental cellular process, facilitates the internalization of extracellular substances and membrane components, maintaining cellular homeostasis and regulating signal transduction. While conventional clathrin-mediated endocytosis (CME) is well understood, the mechanisms of clathrin-independent endocytosis (CIE) remain less explored. Among CIE pathways, the Endophilin A3 (EndoA3)-mediated endocytic route has been identified as critical for the internalization of immunoglobulin-like proteins such as ALCAM in cancer cells. These proteins are involved in immune synapse formation, a polarized structure essential for T cell activation. This thesis first investigates whether Intercellular Adhesion Molecule 1 (ICAM1), another immunoglobulin-like protein and crucial immune synapse component, is an EndoA3-dependent cargo. Then, we explore the role of EndoA3-mediated endocytosis and retrograde transport in immune synapse formation and its impact on anti-tumor CD8 T cell activation. Our findings reveal that ICAM1 is indeed internalized through EndoA3-mediated endocytosis and, like ALCAM, undergoes retromer-dependent retrograde transport to the trans-Golgi network (TGN). Disruption of EndoA3-mediated endocytosis and subsequent retrograde transport in cancer cells impairs the recruitment of ICAM1 to the immune synapse and diminishes T cell activation. These results highlight the critical role of EndoA3-mediated endocytosis and retrograde transport in maintaining the polarized distribution of immune synapse components, providing new insights into potential therapeutic strategies for enhancing cancer immunotherapy.
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Xu, S. (2025). Endophilin A3-mediated clathrin-independent endocytosis and retrograde transport in cancer cells promote cytotoxic CD8 T cell activation. https://hdl.handle.net/2078.5/245640