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）是在婴儿和儿童中发展的恶性致命肿瘤。组蛋白编码基因的突变干扰表观遗传调控，并与其他癌基因共同促进肿瘤的发生和发展。pHGG生长迅速且具有扩散性，这使得它们难以去除或治疗。手术（在中线脑区域无法实现）和放疗（RT）仍然是具有短暂益处的唯一选择，因为中位生存期为9-15个月。这些肿瘤是免疫抑制的，因此免疫疗法是无效的。我们提出，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，从而找到根除突变肿瘤细胞的新方法，提高RT的疗效，并重振抗肿瘤免疫力。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研究大范围pHGG患者样品中的肿瘤-免疫细胞相互作用; ii）创建日益复杂的细胞和动物模型：人类神经胶质瘤-小胶质细胞共培养物、补充有iPSC衍生的免疫细胞的DIPG衍生的类器官和同基因pHGG小鼠模型，其将成为机制研究和药物筛选的平台; iii）评估肿瘤-宿主相互作用的缺氧诱导的表观遗传抑制剂和阻断剂，以改善RT和免疫治疗反应; iv）产生功能化的纳米载体，以靶向免疫细胞并将药物递送至大脑; v）开发更有效的CAR-T细胞，其与TME重编程和RT一起将增强抗肿瘤免疫力; vi）评估疾病的神经发育改变和心理后果，并促进心理方法，以提高患者和护理人员的生活质量。HIT-GLIO的预期结果最终将为新的临床试验铺平道路，以改善pHGG的治疗方式。这一行动是癌症使命“理解（肿瘤-宿主相互作用）”项目组的一部分。

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).