Inhibition of cell death is traditionally considered as a central feature of malignant transformation as well as therapy resistance in cancer patients. However, current research shows that cell death is not only a quantitative response to cell proliferation but also qualitatively dictates the functions and responses of the surrounding tissue through the release of various mediators (e.g. cytokines). Today, we know that a number of different cellular machineries ultimately leading to the common endpoint “cell death” but emit distinct signals for the surrounding tissues. We recently identified Caspase-8 (Casp8, primarily identified as the initiator caspase of apoptosis) as a molecular switch regulating different types of cell death, predetermining the release of various cytokines and ultimately involving diverse tissue responses.

Casp8 controls extrinsic apoptosis and cytokine production following activation of members of the tumour necrosis factor receptor superfamily (TNF-R family). Targeted elimination of tumor cells in the body occurs following activation of TNF-R by cytolytic immune cells (e.g. T cells), which has recently been successfully applied therapeutically in cancer patients through the design of CAR-T cells (Chimeric Antigen Receptor T Cell). However, the intrinsic resistance mechanisms of the tumor cell reduce the effectiveness of such therapeutic interventions, suggesting that simultaneous targeting of tumor cell intrinsic resistance mechanisms is a necessary addition for successful cellular immunotherapy in cancer patients. By using animal models and CAR-T cell technology this project aims to investigate the therapeutic significance of Casp8 in cellular immunotherapy.