Project Details
Projekt
Overcoming T-cell exhaustion in PDAC: NLRP3 inflammasome-dependent effects on T cell function in pancreatic carcinoma
Subject Area
Gastroenterology
Term
since 2017
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 329116008
NLRP3 and NLRP3-dependent cytokines IL-1β and IL-18 play a promoting role in pancreatic cancer, however, direct impact of IL-1R and IL-18R signaling on CD8+ cytotoxic T cells (CTLs) has not been characterized so far. By adoptively transferring IL-1R-, IL-18R-deficient or wild-type (WT) CTLs into mice bearing subcutaneously implanted pancreatic cancer cells stably transfected with model antigen OVA, we found that T cell-intrinsic IL-18 signaling suppressed CTL-mediated pancreatic cancer rejection. Adoptively transferred, intratumoral WT CTL were characterized by enhanced expression of co-inhibitory molecules PD-1 and TIM-3, reduced expression of IFN-γ and TNF after OVA restimulation, and changes in the levels of transcription factors including T-BET, EOMES and TOX, indicative of T cell exhaustion. These effects were partially reversed in transferred Il18r-/- CTL. Here, we plan to investigate the mechanism of T cell-intrinsic IL-18R-deficiency in pancreatic carcinoma. Molecular analysis such as RNA-Seq and ATAC-Seq will be performed. In vivo/in situ multiphoton microscopy will reveal differences in migration pattern and cellular interaction between Il1r-/-/Il18r-/- versus WT CTLs, building upon an established dorsal skinfold chamber model of intratumoral T cell visualization. Furthermore, the role of CD8+ T cell plasticity towards a Tc17 phenotype will be investigated in models of pancreatic carcinoma. This is based on our recent finding that Tc17 cells enhance proliferation of pancreatic tumors via induction of inflammatory cancer-associated fibroblasts (iCAFs). Reciprocal cross-talk between Tc17 cells, tumor cells and iCAFs will be characterized in vitro, in the mouse model and in patients.
DFG Programme
Clinical Research Units
