Periodic Reporting for period 1 - HIT-GLIO (Targeting tumour-host interactions in paediatric malignant gliomas to reinvigorate immunity and improve radio- and immunotherapy efficacy)
Periodo di rendicontazione: 2023-12-01 al 2025-05-31
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 cells that 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.
The aims of HIT-GLIO are to dissect the poorly-understood tumour-host interactions in paediatric high-grade gliomas (pHGGs) with single-cell omics and multi-modal imaging, and develop strategies to enhance immunotherapy and radiotherapy (RT) response. Our project has three main objectives to achieve these aims:
Objective 1. The comprehensive characterisation of tumour-host interactions in human pHGGs.
Objective 2. Development and in-depth characterisation of cellular and mouse models of pHGG to determine tumour-host interactions and identify potential therapeutic targets.
Objective 3. Development and testing of innovative technologies targeting tumour-host interactions to boost immunotherapy and RT response in pHGGs.
The aims of HIT-GLIO are to dissect the poorly-understood tumour-host interactions in paediatric high-grade gliomas (pHGGs) with single-cell omics and multi-modal imaging, and develop strategies to enhance immunotherapy and radiotherapy (RT) response. Our project has three main objectives to achieve these aims:
Objective 1. The comprehensive characterisation of tumour-host interactions in human pHGGs.
Objective 2. Development and in-depth characterisation of cellular and mouse models of pHGG to determine tumour-host interactions and identify potential therapeutic targets.
Objective 3. Development and testing of innovative technologies targeting tumour-host interactions to boost immunotherapy and RT response in pHGGs.
We have started to generate some results in most WPs in our project, including:
- collection and characterisation of patient's biopsies, cerebrospinal fluid (CSF) and retrospective pHGG tissue sections for detailed molecular analysis
- initial results on immune components and interactions wit pHGGs in patient's samples and immunooganoids
- detailed mechanistic studies on pHGG-microglia interaction in cocultures in vitro
- development and optimisation of mouse models to study pHGG-immune cell interactions and future testing of proposed therapies
- development of first nanocariers that could be further optimised to deliver specific targeting (e.g. via siRNAs or peptides) of pHGG-microglia interactions
- validation of hypoxia-targeting and/or radiosensitising drugs for pHGGs
- development of dual CAR T cells for targeting p32, B7H3 and GD2 in pHGGs
- preparing documents and all ethical and administartive requirements for neuropsychological and psychosocial characterization of pediatric high-grade glioma (pHGG), with the broader aim of improving the quality of life of both patients and families
- collection and characterisation of patient's biopsies, cerebrospinal fluid (CSF) and retrospective pHGG tissue sections for detailed molecular analysis
- initial results on immune components and interactions wit pHGGs in patient's samples and immunooganoids
- detailed mechanistic studies on pHGG-microglia interaction in cocultures in vitro
- development and optimisation of mouse models to study pHGG-immune cell interactions and future testing of proposed therapies
- development of first nanocariers that could be further optimised to deliver specific targeting (e.g. via siRNAs or peptides) of pHGG-microglia interactions
- validation of hypoxia-targeting and/or radiosensitising drugs for pHGGs
- development of dual CAR T cells for targeting p32, B7H3 and GD2 in pHGGs
- preparing documents and all ethical and administartive requirements for neuropsychological and psychosocial characterization of pediatric high-grade glioma (pHGG), with the broader aim of improving the quality of life of both patients and families
We have optimized a custom panel of 45 antibodies for CITEseq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing. It's a method for simultaneously measuring both gene expression and cell surface protein levels in individual cells using single-cell RNA sequencing techniques combined with antibody-derived tags. The use of CITE-seq has not been reported yet for the analysis of immune components of pHGGs and is likely to provide additional insitgth on distinct immune cell populations present in these cells. Once optimised, the use of immuno-organoids may provide "patient's avatars" for the future personalised drug testing.