PhD defence M.L. (Mandy) van Gulijk

Below is a brief summary of the dissertation:

Cancer is one of the leading causes of death and the global burden of cancer is predicted to increase to approximately 30 million new cases by 2040. The introduction of a new type of therapy, termed immunotherapy, has created a monumental breakthrough in cancer treatment. Despite being effective in a subset of patients with cancer, the majority of patients treated with immunotherapy do not experience durable clinical benefit. Therefore, it is of great importance to identify how immunotherapy exactly works and why it is not effective in the majority of patients.

The results presented in this thesis formally identifies the importance of lymph nodes that are closely connected with the tumor, the tumor-draining lymph nodes, in orchestrating anti-tumor immunity. In addition, we identified a novel and important mechanism that underlies therapy resistance to anti-PD-1/PD-L1 immune checkpoint blockers (ICB). Anti-PD-L1 antibodies appeared to be able to activate regulatory T cells, an important cell subset that can suppress the immune system, thereby mitigating the activating effects of these ICBs on the immune system. Lastly, we found that the efficacy of dendritic cell therapy can be improved by combination with ICB and with an inhibitor of janus kinase 3.

Together, the results presented in this thesis provide novel and important insights in the mode of action and mechanisms of resistance to immunotherapies, with a focus on ICB and DC therapy. These insights could offer novel avenues for improving existing strategies and could pave the way for the emergence of novel immunotherapies.