Periodic Reporting for period 3 - RegSign (A multi-parametric Regulatory T cell Atlas in cancer to predict immunotherapy response, adverse autoimmune events and to identify novel therapeutic targets)
Periodo di rendicontazione: 2024-01-01 al 2025-06-30
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.
We have completed the recruitment and collection of our discovery cohort, consisting of samples isolated from newly diagnosed individuals experiencing advanced metastatic melanoma. Aiming to generate a high-dimensional single-cell atlas of Tregs in order to develop a “liquid” biopsy predicting immunotherapy efficacy and incidence of autoimmune toxicities induced by these therapies (broadly termed as irAEs: immune related adverse events), we have isolated Tregs and have successfully finalised the single cell multi-omic analysis of all the samples. We have designed and developed customised pipelines, adjusted to our specific experimental needs, for the bulk omic assays and we are currently completing the analysis. Thus far our results provide a comprehensive high-dimensional profile of circulating Tregs at the single-cell level, that enables the identification of promising specific signatures of Treg functional characteristics, with the potential to precisely predict response to immunotherapy and development of autoimmune toxicities. Moreover, exploring Treg-specific traits in individuals with melanoma experiencing autoimmune toxicities post-immunotherapy and projecting these results to Treg functionality during autoimmunity, enabled us to identify selective metabolic programs driving Treg dysfunction in both disease settings. Our findings suggest that inflammatory Treg reprogramming is a feature of immunotherapy-induced autoimmunity, that could be targeted for selective therapy in cancer and thus facilitate translational approaches aiming to induce robust anti-tumour immunity without disturbing peripheral tolerance. Interestingly, leveraging innovative mouse models developed by RegSign we evaluated these latent therapeutic targets in melanoma. Ours results unveil their potential to inhibit the suppressive function of Tregs in the tumour while leaving their peripheral function unaffected a conceptual characteristic that could restrain tumour development and concomitantly block the possible occurrence of autoimmune side effects.
Molecular diagnostics, personalised therapy and identification of novel immunotherapeutic regimens inducing a robust clinical response remain unmet needs in oncology. RegSign aims to generate a translational spin to bridge basic science to those unmet needs with the ambition of answering fundamental research questions and providing diagnostic tools to predict response to treatment and improve the quality of care for cancer patients. RegSign’s results will broaden our awareness beyond the state of the art, using sophisticated multi-disciplinary approaches, in order to provide a comprehensive analysis of Tregs that represent one of the main obstacles towards designing effective immunotherapies. Despite the pivotal importance of Tregs in tumour progression, response to immunotherapy and their potential role as therapeutic targets, their properties in human tumours remain largely unknown. Specifically, the molecular and functional features of Tregs in patients responding to immunotherapy and their role in predicting the risk of developing autoimmune toxicities are highly unexplored. Moreover, whether intratumoral Tregs have unique signatures compared to circulating Tregs, enabling targeted therapy without the risk of inducing systemic adverse effects, remains elusive. RegSign sets the stage for exploring novel concepts in cancer such as the role of circulating Tregs to serve as a “liquid” biopsy for predicting response to immunotherapy and development of autoimmune manifestations. This holds tremendous societal and economic impacts with important implications in cancer diagnosis and management, by contributing to the improvement of the therapeutic outcome for individual cancer patients. RegSign will generate innovative tools, such as humanized mice carrying patient tumour specimens and immune compartments, enabling the development and testing of new and personalised immunotherapeutic targets. The discovery of novel immunotherapy-imprinted traits on Tregs leading to autoimmunity holds obvious clinical implications. In addition, identifying unique signatures of intratumoral Tregs opens new horizons for designing precise immunotherapies to fight tumours without the caveat of autoimmune adverse events. Finally, RegSign will tackle with a pioneering concept of modulating Treg metabolism to adjuvant antitumour immunity while keeping in track hazardous attacks on self-tissue, that will generate breakthroughs in management of cancer and irAEs.