Host Protective Engineering of Cancer Immunity by Targeting the Intracellular Immune Checkpoint NR2F6

Obiettivo

"Because of its biological complexity, cancer is still poorly understood. Chronic inflammation has been shown, both experimentally and epidemiologically, to be a predisposition to, and also an inseparable aspect of clinically prevalent cancer entities. Therefore, a detailed understanding of both tumour and immune cell functions in cancer progression is a prerequisite for more successful therapeutic startegies. My team was the first to reveal the lymphocyte-intrinsic PKC/NR2F6 axis as an essential signalling node at the crossroads between inflammation and cancer. It is the mission of this project to identify molecular signatures that influence the risk of developing tumours employing established research tools and state-of-the-art genetic, biochemical, proteomic and transcriptomic as well as large scale CRISPR/Cas9 perturbation screening-based functional genomic technologies. Defining this as yet poorly elucidated effector pathway with its profoundly relevant role would enable development of preventive and immune-therapeutic strategies against NSCLC lung cancer and potentially also against other entities. Our three-pronged approach to achieve this goal is to: (i) delineate biological and clinical properties of the immunological PKC/NR2F6 network, (ii) validate NR2F6 as an immune-oncology combination target needed to overcome limitations to ""first generation anti-PD-1 checkpoint inhibitors"" rendering T cells capable of rejecting tumours and their metastases at distal organs and (iii) exploit human combinatorial T cell therapy concepts for prevention of immune-related adverse events as well as of tumour recurrence by reducing opportunities for the tumour to develop resistance in the clinic. Insight into the functions of NR2F6 pathway and involved mechanisms is a prerequisite for understanding how the microenvironment at the tumour site either supports tumour growth and spread or prevents tumour initiation and progression, the latter by host-protective cancer immunity."