Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Kienzl, M.
Regulation of immune cells in the tumor microenvironment: the role of IL-33 and 2-AG
PhD-Studium (Doctor of Philosophy); Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 125
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Böhm Eva
- Schicho Rudolf
- Strobl Herbert
- Altmetrics:
- Abstract:
- Tumors exist in an organ-like system with a variety of non-tumor cells with complex cell interactions, termed the tumor microenvironment (TME). The TME comprises a combination of immune cells, non-immune stromal cells, and a plethora of acellular components, which can contribute to tumor development. By influencing the shape of the TME, those acellular components may shift the delicate balance of tumor control towards immune surveillance or escape. This cumulative dissertation focuses on the influence of soluble mediators on components of the TME and their effects on tumor progression. In particular, the investigated mediators have been shown to exert potent immunomodulatory functions. The alarmin IL-33 and components of the endocannabinoid system (ECS), with a focus on the 2-arachidonoylglycerol (2-AG)/monoacylglycerol lipase (MGL)-axis, are addressed in the three included publications: - In the first publication we explored the immunomodulatory effect of IL-33 in a heterotopic and chemically induced colitis-associated colorectal cancer (CRC) model. IL-33 treatment of mice reduced the tumor growth of CRC in both models. Importantly, tumor size reduction was dependent on the presence of eosinophils in the TME. Furthermore, we showed that IL-33 activation directly resulted in increased survival, degranulation, and migration of eosinophils towards CRC. - Components of the ECS are known for their ability to mediate immune cell functions but also directly affect tumor cell behavior. Herein, a comprehensive review article explores the literature about the ECS in the context of the TME and examines possible effects on tumor progression. (Endo)cannabinoids may be potent mediators influencing the state of the TME. - The role of MGL expression in tumor pathogenesis, has been comprehensively studied, however, its influence in the TME remains elusive. We used a heterotopic non-small cell lung cancer (NSCLC) model in a MGL deficient mouse to investigate the effects of MGL and its substrate 2-AG on the state of the TME. Interestingly, MGL deficiency in the TME reduced NSCLC growth and was accompanied by increased levels of 2-AG and enhanced eosinophil and CD8+ T effector cells. We found that 2-AG mediates recruitment and activation of eosinophils and CD8+ T cells in vitro, thus contributing to an anti-tumorigenic TME. In summary, the investigated mediators are promising targets for the induction of an anti-tumorigenic environment and may be an option as adjuvants during immunotherapy.