Online Ph.D Defence by Marlene Fyrstenberg Laursen
Marlene Fyrstenberg Laursen will defend her PhD thesis: "Activating the STING pathway: A potential strategy for anti-cancer immunotherapy?"
24.06.2020 kl. 13.00 - 16.00
13.00 Opening by the Moderator
13.05 PhD lecture by Marlene Fyrstenberg Laursen
14.00 Questions and comments from the Committee
Questions and comments from the audience at the Moderator’s discretion
16.00 Conclusion of the session by the Moderator
Due to the current circumstances the Ph.D defence will take place online via Skype for Business. If you wish to attend, please send an email to Kristine Uldal Knudsen before 22. June 2020 at 12:00.
The Faculty Council has appointed the following adjudication committee to evaluate the thesis and the associated lecture:
Researcher Gunnveig Grødeland
University of Oslo
Professor Thomas Vorup-Jensen
Associate Professor John Dirk Nieland
Professor Svend Birkelund
Immunity and cancer are known to be linked together in a close relationship. The knowledge of how the immune system interacts in tumor development and elimination has led to a revolution in cancer treatment with development of anti-cancer immunotherapy. The potential of immunotherapy against cancer has been confirmed by checkpoint blockade therapy, which can increase survival of cancer patients, by lifting the suppression of T cell responses that is generated by the cancer cells. However, some patients still fall short in responding to the treatment, and development of new approaches to supplement the function of checkpoint blockade is of high interest. Dendritic cells (DCs) are highly involved in immune regulation of cancer, specifically since they are professional antigen-presenting cells and T cell activators and able to shape the character of the immune response. During anti-cancer immune responses, type I interferons (IFN-I) have been shown to be important in the activation of DCs and to increase their ability to mediate T cell dependent tumor rejection. The molecule Stimulator of Interferon Genes (STING) is a major facilitator of IFN-I production in many different cell types, including DCs. Targeting DCs and STING to increase IFN-I production and immune activation could therefore potentially be a way to enhance anti-cancer immune reactions.
The possibility of utilizing DCs and STING in immunotherapeutic cancer treatment was investigated through two studies. In the first study, an adjuvant construct targeted to DCs was generated. The construct consisted of an antibody specific for DC surface molecule CD11c which was conjugated with dsDNA, a known activator of STING, and the maturation status of the cells was determined. Here it was seen that targeting STING with dsDNA in DCs led to a STING-dependent increase in maturation and enhanced their ability to stimulate T cells. In the second study, direct STING agonist, cyclic GMP-AMP (cGAMP), were used together with different cholesterol inhibitors to activate DCs and macrophages. It was found that cholesterol inhibitor treatment led to an increased STING sensitivity to cGAMP treatment, due to increased ER sequestering of STING. The combination treatment with cGAMP and cholesterol inhibitors strongly increased the maturation of human and murine DCs and the activation of human macrophages in vitro. When cholesterol inhibition therapy was applied in vivo for treatment in a murine tumor model, a reduction in tumor growth was detected.
Collectively, these studies indicate that activation of DCs in a STING dependent manner is possible by targeting dsDNA directly to the cells, or by exposing the cells to cGAMP. Furthermore, in the latter situation, the maturational response can be enhanced by the addition of cholesterol inhibitors. Possibly, these methods of increasing the T cell-activating capacity of DCs could be a valuable addition to immunotherapeutic treatment against cancer.
HST - Department of Health Science and Technology
Skype for Business
22.06.2020 kl. 12.00