Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment of glioblastoma

Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) have been associated with acquired resistance to temozolomide and with a high tumor mutation burden (TMB) in high-grade gliomas (HGG), including glioblastoma (GBM). However, the specific roles of individual MMR genes in the initiation, progression, increased TMB and microsatellite instability (MSI), and resistance to temozolomide (TMZ) in glioma have not been extensively studied. In the present study, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, we found that loss of Msh2 or Msh6 does not lead to a high TMB and MSI nor confer response to anti-PD-1 in GBM. Our data also revealed that germline MMRd leads to the transition from low to high-grade glioma. Additionally, we show that mice with germline MMRd had reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect was tumor cell intrinsic but was associated with MMRd in the tumor immune microenvironment, which led to increased immunosuppressive pathways in myeloid cells, reduced lymphoid infiltration, and increased exhaustion of CD8+ T cells. We have found that both MMR-reduced (MMRr) and MMRd GBM are resistant to TMZ, unlike MMRp tumors. Our study shows that KL-50, a new imidazotetrazine-based DNA targeting agent designed to induce DNA interstrand cross-links, is effective in treating both germline and somatic MMRr and MMRd GBM-bearing mice. These findings present a new treatment option for HGG patients with inherited or acquired MMRd who are resistant to TMZ.