Regulatory T cells (Tregs; pronounced 'tee-regs'), are a critical negotiator in the body’s immune response. ‘Killer’ and ‘helper’ T cells fight pathogens or infection and when the threat is over, Treg cells send the signal to stand down. They rein in rogue T cells that attack normal tissues in the body causing autoimmune manifestations. As such, Treg cells have been identified as a therapeutic target for diseases and conditions ranging from multiple sclerosis and cancer to wound repair and hair loss.
Treg cells have been an important area of research in immuno-oncology for over a decade. When stimulated, the immune system can be trained to attack tumours or cancerous cells. If Tregs suppress the immune response, this cancer-fighting mechanism is handicapped. But as new research published in Nature Immunology suggests, interfering in Treg activity doesn't always help as might be predicted. Not only was the immune response not protected, but researchers found that when Tregs were eliminated, their immunosuppressive effect increased.
‘When Tregs die, instead of being negated, they become even more suppressive. All the cells are dead but the machine is still running.’
The study postulates that when Treg cells are killed, they release the metabolite ATP (adenosine triphosphate) and quickly convert it to adenosine. The adenosine then targets T-cells, binding to a receptor on the T-cell surface which inhibits their function. This might help to explain why a smaller number of cancer patients respond to immunotherapy than is expected or hoped.
Treg activity is a hot area in autoimmune research and immune checkpoint regulation in oncology. Celgene and Eli Lilly in particular have invested heavily in Treg stimulators. Earlier this year, Celgene spent $300 million USD on Delinia, whose lead candidate could be used to target autoimmune conditions such as lupus and rheumatoid arthritis. And more recently, Lilly paid $150 million up front to co-develop a Treg booster with Nektar Therapeutics. Biotech company, TxCell, is investing heavily in a breakthrough CAR-Treg technology showing promise in organ transplantation. Novartis is engaged in at least four pre-clinical studies in Treg modulation, and FLX Bio, an American immuno-oncology research company, in partnership with Celgene, expects to begin clinical trials of a novel Treg regulator in cancer treatment this year.
Currently, the best of method of Treg modulation is yet to be determined and many questions are still unanswered. However, the future role of Treg, as either diplomat or detractor, within the remit of both autoimmune disorders and immuno-oncology, looks very promising.
‘Researchers have uncovered a surprising process within a key immune cell that may help explain the limitations of immunotherapy as a cancer treatment.’