Abstract 1451: Replication repair deficient mouse models provide insights into gliomagenesis and response to immunotherapy
Authors: Zoya Aamir, Melissa Galati, Emma Gattoni, Owen Crump, Nuno M. Nunes, Anirban Das, Nicholas Fernandez, Nicholas Fernandez, Angel K. Wong, Jerome Fortin, Lucie Stengs, Vanessa Bianchi, Melissa Edwards, Logine Negm, Cynthia Hawkins, David Malkin, Sean Egan, Uri Tabori
Journal: Cancer Research (2024)

Abstract Background: Replication Repair Deficiency (RRD), caused by germline monoallelic (Lynch Syndrome) or biallelic (Constitutional Mismatch Repair Deficiency, CMMRD) mutations in MMR genes, is present in 5-10% of glioblastomas in children, adolescents, and young adults. RRD glioblastomas are chemoradiation-resistant, but respond favorably to immune checkpoint inhibition (ICI). Representative immunocompetent animal models are urgently needed for 3 recently identified subgroups based on specific somatically-acquired mutations, survival, and immunotherapy response (RRD1: MMRD with POLE mutations, RRD2: MMRD associated with TP53 mutations, and RRD3: MMRD harboring IDH1 mutations). Methods: Using germline mutations and brain-specific Cre-drivers, we genetically engineered mouse models that recapitulate each human RRD-subgroup. Results: All mouse models robustly developed brain tumors displaying phenotypic variation. RRD1 (Nestin- and Olig2-Cre+/Msh2LoxP/LoxP/PoleS459F/+ and LSL-PoleP286R/+): CMMRD-like Nestin-Cre-driven mice develop posterior-fossa glioma-like or embryonal (EB)-like tumors at ~2.7 months. Olig2-Cre-driven mice display hemispheric gliomas at ~10 months, suggesting distinct cell-of-origin. RRD2 (Nestin-Cre+/Trp53LoxP/LoxP and Msh2LoxP/LoxP or Mlh1−/−): tumors develop primarily in the hindbrain in germline Mlh1 mice, and majority arise in the forebrain of Nestin-Cre/Msh2 mice, highlighting the timeline of mutagenesis. Strikingly, germline Mlh1 tumors occur earlier than Nestin-Cre-driven RRD2 tumors, indicating early developmental mutation accumulation in CMMRD-patients. Lynch-like RRD1/2 mice succumb exclusively to gliomas &amp;gt;13 months (p&amp;lt;0.0001). RRD3 (Olig2-Cre+/Msh2LoxP/LoxP/Trp53LoxP/LoxP/LSL-Idh1R132H/+): mice succumb to brain tumors at &amp;gt;11 months and are hemispheric. Significance: These observations recapitulate human data, where CMMRD-patients develop glioblastoma/EB earlier than Lynch-patients (8.6 vs. 14-years; p&amp;lt;0.0001), and posterior-fossa glioblastoma/EB presents earlier than hemispheric gliomas (p=0.04). Additionally, tumor onset and location vary by subgroup (RRD1: 7.6-years, RRD2: 8.3-years, both hemispheric/posterior-fossa; RRD3: 12-years, hemispheric; p=0.005). In both mice and humans, RRD1 exhibits ultra-hypermutation, high immune infiltration, and response to ICI, whereas RRD2 harbors lower mutational burden, are immune-cold, and ICI-monotherapy resistant. Temporal dynamics of RRD tumor development is currently being tracked by serial MRI to define previously undetermined biologically relevant time points of tumor progression. Conclusion: Our models accurately mimic the human condition and provide unique insights into RRD tumorigenesis, allowing optimization of subgroup-tailored therapeutic approaches. Citation Format: Zoya Aamir, Melissa Galati, Emma Gattoni, Owen Crump, Nuno M. Nunes, Anirban Das, Nicholas Fernandez, Nicholas Fernandez, Angel K. Wong, Jerome Fortin, Lucie Stengs, Vanessa Bianchi, Melissa Edwards, Logine Negm, Cynthia Hawkins, David Malkin, Sean Egan, Uri Tabori. Replication repair deficient mouse models provide insights into gliomagenesis and response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1451.