Researchers at Oxford University have discovered nanoscale contact points where T-cells decide whether to attack a tumor or retreat, according to a study published in Science Immunology, reports infohub.kz.
Every interaction between a T-cell and a potential target begins with a rapid series of molecular decisions. Within seconds, the immune cell must determine whether to launch an attack or pull back. T-cells are incredibly powerful, so a misjudgment can cause significant tissue damage. But cancer cells have a repertoire of tricks to disarm the immune system, all unfolding at the cell contact point.
T-cells interact with their environment through finger-like projections called microvilli, which form nanoscale tight contacts with target cells. These contacts contain T-cell receptors and immune checkpoints such as PD-1. Scientists have been trying to understand how cells integrate opposing signals from different receptors.
The researchers modified various parameters, including receptor number, domain length, ligand binding affinity, and cell morphology. They found that immediately after tight contact forms, the PD-1 signaling pathway activates, suppressing T-cell activation. At the contact point, a tumor cell can engage the PD-1 receptor on the T-cell surface, triggering an inhibitory signal that prevents tumor destruction. This trick allows cancer to proliferate while evading the immune system.
After activation, PD-1 blocked the formation of additional tight contacts and recruited the signaling molecule SHP2, which limited the duration of T-cell receptor signaling. The study also showed that under certain conditions, the PD-1 checkpoint inhibitor nivolumab briefly activated the same pathway it is meant to block. Scientists believe this discovery could serve as a foundation for next-generation drugs targeting immune checkpoint inhibitors.