En Pointe: Composing novel immunotherapy strategies to improve systemic anti-tumor immunity

Research output: Types of ThesisDoctoral ThesisInternal

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Abstract

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. To increase the efficacy of immunotherapy, extensive research has focused on the tumor microenvironment (TME), but these efforts have not yet resulted in substantial improvements in therapeutic efficacy. The significance of coordinating regulation across various tissues is becoming apparent, highlighting the roles of the spleen, bone marrow, gut microbiome, and the tumor-draining lymph node (TDLN) in establishing systemic anti-tumor immunity. Understanding the dynamic coordination between cell types and their location in orchestrating anti-tumor immunity could provide novel insights in the requirements for an effective response to immunotherapy. Therefore, the aim of this thesis was to acquire in-depth understanding of mechanisms underlying the effectiveness and resistance of different immunotherapy strategies – immune checkpoint blockade (ICB) and dendritic cell (DC) therapy - by adopting a wider perspective of the systemic anti-tumor immune response.

The results presented in this thesis highlight the importance of the tumor-draining lymph node (TDLN) in orchestrating anti-tumor immunity. More specifically, the TDLN appeared to be important in dictating the efficacy of anti-PD-1/PD-L1 immune checkpoint blockade. The importance of TDLN biology in establishing effective anti-tumor immunity was further underlined by findings showing that differences in TDLN immune contexture could underlie effective anti-tumor immunity as an immunosuppressive environment in the TDLN was related to disease recurrence in patients with melanoma. Besides a deeper understanding of the mechanisms of action, we also aimed to unravel novel mechanisms responsible for therapy resistance. To this end, we identified that anti-PD-1/PD-L1 immune checkpoint blockade could systemically activate regulatory T cells, causing therapy resistance in the process. Lastly, results presented in this thesis show that combining DC therapy with either anti-PD-1/PD-L1 immune checkpoint blockade or inhibition of janus kinase 3 could improve the efficacy of DC therapy.

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 anti-PD-1/PD-L1 immune checkpoint blockade and DC therapy. Importantly, these findings highlight that the effectiveness of immune responses directed at tumor cells is shaped by the intricate interactions among multiple tissues, rather than being exclusively dictated by conditions at the tumor site. These insights could offer novel avenues for improving existing strategies and could pave the way for the emergence of novel immunotherapies.
Original languageEnglish
Awarding Institution
  • Erasmus University Rotterdam
Supervisors/Advisors
  • Aerts, Joachim, Supervisor
  • van Hall, Thorbald, Supervisor, External person
  • Dammeijer, Floris, Co-supervisor
Award date12 Jun 2024
Place of PublicationRotterdam
Print ISBNs978-94-6483-984-5
Publication statusPublished - 12 Jun 2024

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