T-Zell-Dysfunktion im Pankreaskarzinommodell: Rolle der IL-18- und IL-1- Rezeptor-Signaltransduktion bei der Induktion intratumoraler T-Zell-Dysfunktion

Pancreatic cancer is characterized by low immunogenicity and low antigenicity, resulting in limited success of immunotherapy such as checkpoint inhibitor therapy in clinical trials. Intratumoral CD8+ cytotoxic T cells (CTLs) exhibit a dysfunctional status (also known as exhaustion), characterized by impairment of cytokine production as well as upregulation of co-inhibitory receptors, such as PD-1 and TIM-3. This results in the loss of T cell effector function. Mechanistically, proinflammatory cytokines IL-1β and IL- 18 might influence intratumoral T cell plasticity. This project investigates the role of NLRP3-mediated IL-1 receptor and IL-18 receptor signalling on cytotoxic T cell responses in a murine model of pancreatic cancer. The main aims of this project were: a) to investigate the role of IL-1 and IL-18 signaling in CTLs on their plasticity and cytotoxicity, b) investigate which role IL-1 and IL-18 signaling play in intratumoral CTL on their dysfunctional status in a murine pancreatic cancer model, c) characterize the influence of IL-1 and IL-18 on tumor cells and d) how does intratumoral NLRP3 signaling change the immunresponse of CTLs and which role does it play during exhaustion. This study shows that IL-18R signalling, and to a lesser degree IL-1R signalling, has an immunosuppressive effect on intratumoral CTLs and causes an exhausted phenotype. IL-18R signalling induces this dysfunctional phenotype by IL-2 receptor stimulation, resulting in the activation of the IL-2/STAT5-pathway. IL-18R-deficient intratumoral T cells show reduced expression of Pdcd1, Havcr2, Lag3, Tigit, Eomes and Prdm1 in comparison to WT T cells, with an upregulated expression Tcf7 and Lef1 at the same time. This indicates that Il18r-/- CTLs develop more easily into stemness-like memory cells, instead of exhausted effector CTLs. Furthermore, our study shows a pleiotropic effect of NLRP3 and its mediated cytokines on T-cell activation and exhaustion in the tumor stroma. Thus, this work provides mechanistic insights into NLRP3-mediated IL-1β and IL-18 signalling in CTLs during intratumoral exhaustion and might prove relevant for the development of innovative immunotherapies.