Cancer remains the second leading cause of death globally with a rising burden of 18.1 million new cases and 9.6 million deaths in 2020. Recent breakthroughs in the field of immunology have revolutionised anti-cancer therapy, giving rise to the era of immunotherapy. Immunotherapy, boosts the natural defences of our immune system to destroy cancer cells. Despite noted clinical success, more than half of treated patients do not show beneficial outcomes, whereas responses are often accompanied by life-threatening autoimmune toxicities, suggesting that more precise immunotherapies to advance anti-tumour immunity while keeping in check autoimmune responses are of urgent need. Moreover, as immunotherapies become more common, the occurrence of autoimmune side effects is expected to dramatically rise. Thus, development of predictive biomarkers of immunotherapy response is paramount for optimising treatment selection for each patient. This vision, entails the comprehensive understanding of the mechanisms underlying the limited beneficial effects of immunotherapy and the development of autoimmune toxicities. In light of these requirements, RegSign turns the spotlights on Regulatory T cells (Tregs), the dominant immune suppressive population in the tumour microenvironment, aiming to explore their functional molecular and cellular traits with the ambition of translating these mechanisms into precise therapies and diagnostic tools that improve the quality of care for cancer patients. Tregs, represent an ideal candidate, since they are physiologically engaged in prevention of autoimmunity, restrain aberrant anti-cancer immune responses, correlate with poor prognosis and importantly, represent a fundamental impediment for cancer immunotherapy success. RegSign through a systematic multi-parametric single-cell analysis will set the stage for exploring novel concepts in cancer, like the role of circulating Tregs, to serve as a “liquid” biopsy for predicting clinical response to immunotherapy and development of autoimmune toxicities. Furthermore, this project will generate innovative animal models allowing the development and testing of new immunotherapeutic targets and design of personalised therapy. Finally, by applying a pioneering concept of modulating Treg metabolism to invigorate immune system to fight cancer while keeping in track hazardous attacks on self-tissue, RegSign will generate breakthroughs in the management of immunotherapy-induced autoimmune side effects.
