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Project A1: Overcoming T-cell exhaustion in PDAC: Mechanisms of CD8+ cytotoxic T cell dysfunction in pancreatic carcinoma

Participants:

PD Dr. med. Christian Bauer
Gastroenterology 
University Hospital Marburg

Prof. Dr. rer. nat. Magdalena Huber
Medical Microbiology and Hygiene
Philipps-Universität Marburg

Project aims:

Intratumoral T cells transform into a differentiation state that has been termed T cell exhaustion, which is characterized by upregulation of inhibitory receptors, like TIM-3 and PD-1, resulting in loss of effector function. T cells infiltrate pancreatic ductal adenocarcinoma (PDAC), however, anti-tumor efficacy of these T cells is low. Levels of proinflammatory cytokines are increased in PDAC tissue and might influence T cell effector function. Cytokines IL-1β and IL-18 are activated by the NLRP3 inflammasome complex. Here, we hypothesize that NLRP3 and NLRP3-mediated cytokines IL-1β and IL-18 contribute to the induction of CD8+ T cell dysfunction in PDAC. We will investigate mechanisms regulating intratumoral T cell dysfunction, combining phenotypical, functional and metabolic T cell analysis with multiphoton imaging technology. Our work will focus on experiments in an adoptive T cell transfer model using model antigen ovalbumin (OVA) and OT1 cells expressing a transgenic TCR recognizing OVA. We intend to validate our findings on patient material provided by the biobank. By understanding the impact of pancreas tumor microenvironment on cytotoxic CD8+ T cell effector function, we intend to contribute to the development of new therapy regimens.