EVALUATION COMMITTEE

The Faculty Council has appointed the following adjudication committee to evaluate the thesis and the associated lecture: 

• Senior Researcher, Pierre Guermonprez, Institut Pasteur, France
• Senior Researcher, Anders Elias Hansen, Technical University of Denmark, Denmark
• Associate Professor, Louisa Bohn Thomsen, Aalborg University, Denmark (Chair)

Moderator: Associate Professor, Emil Kofod-Olsen , Aalborg University, Denmark

ABSTRACT

Immunotherapy, mainly immune checkpoint inhibitors, have shown great potential as cancer treatment in a group of patients across different cancer types. Unfortunately, the majority of patients still do not benefit from this treatment. There are several explanations for this lack of effect but one is the lack of cytotoxic T lymphocyte (CTL) activation, the most important cell type in the direct killing of cancer cells. CTLs needs to be presented to tumor associated antigen to exert their functions. This presentation is undertaken by antigen-presenting cells, predominantly dendritic cells (DCs), which themselves need an activation signal. DCs can be activated by uptake of danger signals, such as free DNA originating from cancer cells. Inside the DCs, the DNA will be recognized by the DNA-sensor cGAS, which activate the Stimulator of Interferon Genes (STING) pathway, which further activates the DCs and the surrounding immune cells. This dissertation investigated the effect of priming the STING pathway in DCs and murine tumor models. It was found that STING priming increases activation and concomitant cancer cell death in co-cultures by novel mechanisms unique to DCs. Furthermore, repurposing an FDA approved drug was investigated, showing that it also primes the STING pathway in DCs and leads to decreased tumor growth in syngeneic murine tumor models with increased tumor-infiltration by cDC1, cDC2 and CTLs. Collectively, this dissertation identified novel mechanisms of DC STING priming, proposing a potential of new treatment options in combination with already existing cancer treatments.