Preclinical investigation of strategies to bolster immunotherapy for glioblastoma
16 december 2019
UAntwerp - Campus Drie Eiken - Building O - Auditorium O5 - Universiteitsplein 1 - 2610 WILRIJK (route: UAntwerpen, Campus Drie Eiken
Jorrit De Waele
Prof E. Smits & Prof A. Wouters
PhD defence Jorrit De Waele - Faculty of Medicine and Health Sciences (Presentation in English)
Glioblastoma (GBM) is the most common malignant primary brain tumor and remains one of the most deadliest cancers to date. The long-term standstill in progression of the standard of care in combination with inevitable tumor recurrence and death underscore the urgency of efficacious treatment approaches. The past decade, the interest in immunotherapy for GBM has been invigorated by clinical successes in other solid tumors and a better understanding of immunological mechanisms in the central nervous system. The main objective of this doctoral thesis was to study approaches that could contribute to the unlocking of immunotherapy for GBM and its subsequent implementation in clinical practices.
The greatest immunotherapeutic breakthrough in cancer, i.e. the blockade of immune checkpoints (ICB), remains elusive for GBM. In the first part of this thesis, we sensitized GBM to ICB via polyriboinosinic-polyribocytidylic acid, or poly(I:C). By mimicking a viral infection, poly(I:C) acts as a danger signal to which immune cells become activated. While poly(I:C) contributes to the development of antitumor immunity, it also elicits a desirable safety profile without reported objective protumoral responses in GBM. Our work on primary patient-derived GBM cell cultures elucidated a poly(I:C)-driven pro-inflammatory secretome that resulted in T cell attraction and activation of lymphocytes. As a negative feedback mechanism, GBM cells upregulated programmed cell death 1 ligand 1 or PD-L1, whose blockade further strengthened the immune response.
In the second part of this thesis, we looked at novel approaches that might support immunotherapy in GBM. First, we aimed to target hypoxia via hypoxia-inducible factors (HIF), the primary mediators of the hypoxic response. Hypoxia indeed impaired immune cell-mediated cytotoxicity of GBM cells and modulated the expression of immunomodulatory molecules. However, we were unable to robustly and reproducibly investigate the targeting of HIF, underscoring the need for further optimization to study these intriguing targets for cancer (immuno)therapy. Finally, we investigated cold atmospheric plasma or ionized gas as a novel cancer treatment modality. GBM cell lines died following direct plasma therapy or plasma-activated medium. These results support further research to investigate the effects of plasma with established oncological treatment modalities, e.g. immunotherapy.
In conclusion, this doctoral thesis supports the use of poly(I:C) in ICB as a means to unlock the potential of this highly-investigated immunotherapeutic strategy in GBM. In addition, the foundation was laid for exploring HIF targeting and cold atmospheric plasma treatment appeared as a potentially promising candidate for the (immuno)therapeutic landscape of GBM.