Data from: Clathrin-independent endocytosis and retrograde transport in cancer cells tune immune synapse organization and CD8 T cell response

Endophilin A3-mediated clathrin-independent endocytosis (EndoA3-mediated
CIE) contributes to the internalization of immunoglobulin-like proteins,
including key immune synapse components. Here, we identify ICAM1 as a
novel EndoA3-dependent cargo, alongside ALCAM. We demonstrate that both
proteins subsequently follow retromer-dependent retrograde transport to
the trans-Golgi network (TGN) in cancer cells. From there, we propose that
they undergo polarized redistribution to the plasma membrane, where they
contribute to immune synapse formation between cancer cells and cytotoxic
CD8 T cells. Disruption of EndoA3 or retromer components significantly
affects the response of autologous cytotoxic CD8 T cells, as evidenced by
reduced cytokine production and secretion, but increased lytic activity,
while proliferation and later activation marker expression remain intact.
This is accompanied by diminished ICAM1 density at the immune synapse,
where we observe it arriving via polarized vesicular transport, indicating
altered synapse organization. Indeed, cancer cells lacking EndoA3-mediated
CIE or retromer form enlarged immune synapses that fail to sustain full T
cell cytokine secretion, suggesting a compensatory attempt by T cells to
overcome the defective synapse, while likely promoting more transient
contacts that potentially favor serial killing. Together, these findings
reveal that EndoA3-mediated CIE and retrograde transport act in concert in
cancer cells to relocate immune synapse components via the Golgi, thereby
fine-tuning the balance between cytotoxic T cell cytokine secretion and
lytic activity. These insights contribute to a better understanding of the
mechanisms governing immune synapse formation and organization, providing
a necessary foundation for the long-term identification of new strategies
to enhance T cell–mediated anti-tumor immunity.