The study, published in Science Immunology, shows that signalling through the immune checkpoint protein PD-1 begins within tiny contact points that form when T cells first encounter another cell. The findings also reveal that some PD-1-blocking cancer therapies can unintentionally trigger the very pathway they are designed to block, meaning researchers can look at news way to engineer more effective treatments.
The research was led by Edward Jenkins, Sir Henry Wellcome Postdoctoral Fellow at the Kennedy Institute of Rheumatology, University of Oxford, in collaboration with researchers from the MRC Translational Immune Discovery Unit at Oxford, the University of Cambridge and international partners.
T cells are a vital part of the immune system, helping the body recognise and destroy infected or cancerous cells. To prevent excessive immune responses from damaging healthy tissue, T cells are regulated by built-in molecular 'brakes' known as immune checkpoints.
One of the most important of these immune checkpoints is PD-1. When activated, PD-1 reduces T-cell activity, preventing harmful overreactions by the immune system. Cancer cells can exploit this mechanism by activating PD-1 and effectively switching off the immune response directed against them.
Anti-PD-1 drugs such as nivolumab and pembrolizumab, used successfully as treatments for several types of cancer, work by blocking PD-1, helping T cells remain active and attack tumours. These treatments have transformed outcomes for many patients with cancer, but many people still do not respond, and scientists have not fully understood how PD-1 works at the cellular level.
Using advanced microscopy the researchers investigated what happens when T cells first make contact with another cell.
T cells probe surrounding cells using tiny finger-like projections called microvilli to look for signs of infection or disease. The very first points where these microvilli touch another cell become tiny signalling hubs, which the authors call 'microvillar close contacts'. They found that signalling through PD-1 begins almost immediately making a decision whether to activate or inhibit signals.
Rather than preventing activation from starting, PD-1 acts by shortening how long activation signals last. T cells still begin to respond, but the response is cut short before it can be fully sustained.
The researchers also found that PD-1 suppresses immune responses in two ways. As well as directly dampening signalling inside the T cell, it limits the formation of additional contact points, reducing the cell's ability to maintain a prolonged response.
One of the study's most significant findings relates to the antibodies used to block PD-1 in cancer treatment.
The team discovered that under some circumstances these antibodies can become trapped within the same nanoscale contact regions where PD-1 signalling occurs. When this happens, they can partially activate PD-1 rather than simply blocking it, reducing the effectiveness of treatment.
By engineering modified antibodies that avoided this trapping effect, the researchers were able to improve anti-tumour immune responses in experimental models.
Edward said: 'We found that PD-1 signalling starts at the very first points of contact between a T cell and its target. These tiny contact sites act as decision-making hubs where activating and inhibitory signals are balanced, ultimately determining whether a T cell mounts an immune response.'
He added: 'Our findings show that the physical organisation of receptors at these nanoscale interfaces is just as important as the biochemical signals they generate. By understanding these mechanisms, we have shown that you can design checkpoint therapies that block inhibitory signals more effectively and potentially improve outcomes for patients.'