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

儿科高级别胶质瘤(PHGG)是一种发生在婴儿和儿童身上的恶性、致命性肿瘤。组蛋白编码基因的突变扰乱了表观遗传调控，并与其他癌基因协同促进肿瘤的启动和进展。PHGG生长迅速，扩散迅速，很难去除或治疗。手术(在中线脑区无法实现)和放射治疗(RT)仍然是唯一具有暂时好处的选择，因为中位生存期为9-15个月。这些肿瘤是免疫抑制的，因此免疫治疗无效。我们认为，肿瘤微环境(TME)中肿瘤-宿主相互作用的知识将揭示新的靶点，从而找到新的方法来根除突变的肿瘤细胞，提高RT的效率，并重新激活抗肿瘤免疫。为了实现这些雄心勃勃的目标，我们建立了国际多学科联盟Hit-glio。我们将i)使用最新的单细胞技术和多模式成像来描述PHGG患者大范围样本中肿瘤与免疫细胞的相互作用；ii)创建日益复杂的细胞和动物模型：人胶质瘤-小胶质细胞共培养，DIPG衍生的有机化合物与iPSC衍生的免疫细胞互补，以及同基因PHGG小鼠模型，这将成为机制研究和药物筛选的平台；iii)评估低氧诱导的肿瘤-宿主相互作用的表观遗传抑制剂和阻断剂，以改善RT和免疫治疗反应；iv)产生具有靶向免疫细胞功能的纳米载体，并将药物输送到大脑；V)开发更有效的CAR-T细胞，与TME重新编程和RT一起提高抗肿瘤免疫力；vi)评估神经发育变化和疾病的心理后果，并培养提高患者和照顾者生活质量的心理方法。Hit-glio的预期结果最终将为新的临床试验铺平道路，以改善PHGGs的治疗方式。这项行动是癌症使命“了解(肿瘤-宿主相互作用)”项目集群的一部分。

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).