中枢神经系统发育特异性复制修复缺陷的跨物种分析揭示胶质瘤发生和免疫治疗反应的差异模式

Introduction: Replication repair deficiency (RRD) is a pan-cancer mechanism caused by germline and/or somatically acquired mutations in the replication repair machinery - DNA polymerase proofreading and the mismatch repair (MMR) system. Germline monoallelic (Lynch Syndrome, LS) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes are present in 5-10% of glioblastomas in children, adolescents, and young adults. RRD gliomas are lethal, chemoradiation-resistant cancers, characterized by universal hypermutation and variable susceptibility to immune-checkpoint inhibition (ICI). These tumors exhibit variability in patient age of onset, type, location, and response to ICI. Methods: To understand the clinical and biological differences associated with RRD central nervous system (CNS) tumors, we used germline mutations and brain development-specific Cre -drivers to generate murine models that recapitulate the phenotypic and genomic characteristics of each human RRD subgroup: 1) MMRD+PPD ( Nestin- and Olig2-Cre + / Msh2 LoxP/LoxP /Pole S459F/+ and LSL-Pole P286R/+ ): MMR-deficiency (MMRD) in combination with polymerase proofreading deficiency (PPD). 2) MMRD-only ( Nestin-Cre + /Trp53 LoxP/LoxP and Msh2 LoxP/LoxP or Mlh1 -/- ): MMRD lacking PPD associated with TP53 mutations. Results: Using trans-species comparative approach, we elucidated a mechanistic model of RRD-driven brain tumorigenesis. We revealed that the cell-of-origin significantly contributes to determining brain tumor type, location, and age of tumor onset, suggesting a strong impact of early- or late-RRD mutational onset in shaping tumor biology (p<0.0001). Importantly, using murine neural stem cells, we discovered that germline mutagenesis onset directly influences timeline of brain tumor formation and survival between CMMRD and LS patients (p<0.05). We further demonstrate the interplay between POLE mutations and MMRD status in modulating the likelihood of brain tumorigenesis in both species. To understand the interaction between hypermutation and the immune system, we characterized the tumor immune microenvironment in spontaneously forming tumors. We uncovered subgroup-specific immune landscapes, with CD8 + T cell activity emerging as a key modulator in controlling brain tumor growth (p<0.0001), suggesting an underlying mechanism that may inform therapeutic strategies in RRD patients. Significance: Altogether, our models accurately mimic the human condition, providing a mechanistic framework of RRD-driven brain tumorigenesis, optimization of subgroup-tailored immunotherapy approaches, and putative surveillance protocols.