Trans-species analysis of mismatch repair deficient IDH1 mutant gliomas reveals a unique genomic and immune landscape resulting in favorable response to combination immune and targeted therapy

High-grade gliomas are deadly tumors in children and young adults (CAYA). Mismatch Repair Deficiency (MMRD) is present in 5-10% of CAYA gliomas and is typically associated with favorable response to immune checkpoint inhibitors (ICI). Interestingly, a subset of MMRD-CAYA gliomas harboring IDH1 mutations fails to respond to ICI. At the molecular level, the interaction of MMRD with mutant IDH (mIDH) and the causes of ICI resistance are not well understood. To tackle this challenge and develop effective therapeutic strategies for these cancers, we performed trans-species clinical, multi-omic, and immune analysis of human and murine tumors. Molecularly, MMRD-mIDH gliomas displayed a profile resembling mismatch repair proficient (MMRP) astrocytomas, characterized by frequent TP53 (83%) and ATRX (76%) mutations and absence of oligodendroglioma-associated alterations (1p/19q codeletion). Nevertheless, in contrast to MMRP-mIDH gliomas, which more commonly present as low-grade tumors, >91% of MMRD-mIDH gliomas were high-grade, exhibiting significantly worse outcomes (p<0.001). Compared with MMRD-IDH wildtype gliomas, MMRD-mIDH gliomas exhibited reduced tumor mutation burden (TMB, 113 vs 28 mutations/Mb, p<0.05) and immune infiltration, quantified by Tumor Inflammation Signature and CD8+ T cell density, partially explaining their inferior survival under ICI treatment. In order to study tumor development, metabolic and immune profiles, as well as response to combination therapy, we developed a novel MMRD-mIDH glioma mouse model ( Olig2-Cre + /Msh2 LoxP/LoxP /Trp53 LoxP/LoxP /LSL-Idh1 R132H/+ ). Mouse MMRD-mIDH gliomas displayed characteristic features of human gliomas, including TMB (20 mutations/Mb), altered glioma driver genes ( ATRX, NF1) , diffuse cerebral involvement, and low immune infiltrates (p<0.05) as compared with MMRD-IDH wildtype models. Preliminary data reveals that mIDH inhibition does not impact proliferative and stemness capacity of MMRD-mIDH mouse glioma cells in vitro, while detailed analysis of the effect of mIDH inhibition on genomic, transcriptomic, and immune profiles are ongoing. Strikingly, informed by our trans-species analysis, an initial trial using the addition of IDH inhibitor to ICI (n=13 patients) led to objective radiological responses and prolonged survival at 12-months compared to ICI monotherapy (p=0.01). MMRD-mIDH gliomas are a genetically and biologically distinct group of tumors with limited therapeutic options. Molecular and immune profiling of MMRD-mIDH gliomas, from both patients and a novel mouse model, enables investigation of the biology underlying glioma development and testing of improved therapeutic approaches.