Local and systemic immune interactions in malignant gliomas

Glioblastoma (GBM), the most frequent primary intrinsic brain tumor, is without any doubt one of the most devastating diseases known to mankind. GBM are currently being treated with neurosurgical resection followed by radio- and chemotherapy. However, despite this treatment, prognosis for these patients is grim with a median survival of only 15 months and less than 20% 3-year survival rates. Already at diagnosis, GBM cells are infiltrating beyond the visible tumor margins, making complete resection impossible. A therapy-resistant subpopulation of these remaining cells eventually leads to tumor recurrence. In the past 2 decades, immunotherapy has gained interest as a possible fourth treatment strategy. Immunotherapy is theoretically appealing, firstly because tumor-infiltrating cytotoxic immune cells could target all invasive cancer cells without damaging surrounding normal tissue. Secondly, when immunological memory develops, responses can be long-lasting without the need of persistent administration of therapy. For GBM, these concepts have been shown in preclinical animal models with several vaccination strategies. However, until now no randomized immunotherapy trials have been able to shown survival benefit in humans. In this research project we aimed to get more insight in the complex interactions between the immune system and GBM, in particular the differences in immune profiles between the local tumor micro-environment and the systemic / peripheral compartment. We hypothesize that better understanding on how the immune system interacts with a developing GBM is essential to develop effective immunotherapy, or at least to understand why successful preclinical therapies don't work in the clinical setting. For this research we used tumor tissue and blood samples from glioma patients, as well as the orthotopic murine GL261 malignant glioma model in which malignant brain tumors are induced by stereotactic injection of GL261 cells. In the first part of the research (Chapter 3 - Research paper 1), we focused on the immune checkpoint molecule PD-1 as a contemporary paradigm target for current immunotherapy in several cancers. PD-1 is a surface protein present on activated T-lymphocytes that, after binding with its ligand PD-L1, leads to a negative feedback signal. This pathway is being used by many cancers to suppress infiltrating lymphocytes, and blockade of PD-1 has been shown to reactivate anti-tumor T cells and prolong survival in advanced melanomas and ot