Abstract 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 (PP) and the mismatch repair (MMR) system. Germline monoallelic (Lynch Syndrome) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes are present in 5-10% of glioblastomas in children. RRD gliomas are lethal, chemoradiation-resistant cancers, characterized by universal hypermutation and variable clinical features, including age of onset, tumor type, location, and response to immune checkpoint inhibition (ICI). Methods To understand the clinical and biological heterogeneity associated with these tumors, we used germline mutations and brain development-specific Cre-drivers to generate murine models that recapitulate genetic and biological phenotypes of human RRD subgroups: 1) MMRD+PPD (Nestin-Cre+ or Olig2-Cre+ and Msh2LoxP/LoxP/LSL-PoleP286R/+): MMR-deficiency (MMRD) in combination with PP-deficiency (PPD). 2) MMRD (Nestin-Cre+/Trp53LoxP/LoxP and Msh2LoxP/LoxP or Mlh1-/-): MMRD-only associated with p53 mutations. Results Using a trans-species comparative approach, we revealed that Nestin-Cre+- or Olig2-Cre+-driven RRD result in different brain tumor type, location, and age of tumor onset, suggesting a strong impact of cell-of-origin and early- or late-RRD in shaping tumor biology (p 0.0001). Additionally, germline RRD significantly shortens timeline of brain tumor formation when compared to Nestin-Cre+-driven models (p = 0.006). This accelerated tumourigenesis is fueled by increased mutation accumulation in germline RRD normal murine neural stem cells (NSCs) compared with matched NSCs in developmental driver-driven models of RRD (p = 0.01), highlighting the role of early hypermutation in normal cells of children with CMMRD. Finally, MMRD+PPD murine tumors exhibited increased CD8+ T-cell infiltration compared to MMRD-alone (p = 0.009), identifying CD8+ T-cells as a key modulator in controlling brain tumor growth (p = 0.0001), and providing an explanation for the high response to ICI in MMRD+PPD human tumors. Significance These models accurately mimic the human condition, providing a mechanistic framework of RRD-driven gliomagenesis for optimization of subgroup-tailored immunotherapy and surveillance protocols.
Aamir et al. (Tue,) studied this question.