Targeting tumour-host interactions in paediatric malignant gliomas to reinvigorate immunity and improve radio- and immunotherapy efficacy

Paediatric high-grade gliomas (pHGGs) are malignant, deadly tumours developing in infants and children. Mutations in histone coding genes disturb epigenetic regulation and in cooperation with other oncogenes promote tumour initiation and progression. pHGGs are fast-growing and diffusive which makes them hard to remove or treat. Surgery (unattainable in midline brain regions) and radiotherapy (RT) remain the only option with transient benefits as median survival is 9-15 months. Those tumours are immunosuppressed, thus immunotherapy is ineffective. We propose that knowledge of tumour-host interactions in the tumour microenvironment (TME) would reveal novel targets allowing to find new ways to eradicate mutated tumour cells, improve efficacy of RT, and reinvigorate anti-tumour immunity. To achieve these ambitious goals we built up the international, multidisciplinary consortium HIT-GLIO. We will i) use latest single-cell technologies and multimodal imaging to characterise tumour-immune cell interactions in a large spectrum of pHGG patient samples; ii) create cellular and animal models of increasing complexity: human glioma-microglia co-cultures, DIPG-derived organoids complemented with iPSC-derived immune cells and syngeneic pHGG mouse models which would be platforms for mechanistic studies and drug screening; iii) evaluate hypoxia-inducible epigenetic inhibitors and blockers of tumour-host interactions to improve RT and immunotherapy responses; iv) generate nanocarriers functionalised to target immune cells and deliver drugs to the brain; v) develop more effective CAR-T cellsthat together with TME reprogramming and RT would boost anti-tumour immunity; vi) assess neurodevelopmental alterations and psychological consequences of disease and foster psychological approaches to increase quality-of-life of patients and caregivers. The expected outcomes of HIT-GLIO would ultimately pave ways to new clinical trials to improve the way pHGGs are treated. This action is part of the Cancer Mission cluster of projects on “Understanding (tumour-host interactions).