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

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Abstract

Mutations in DNA mismatch repair (MMR) pathway genes (MSH2, MSH6, MLH1, and PMS2) are linked to acquired resistance to temozolomide (TMZ) and 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, TMB, microsatellite instability (MSI), and resistance to TMZ in glioma remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGG. Surprisingly, loss of Msh2 or Msh6 does not lead to high TMB, MSI, nor confer response to anti-PD-1 in GBM. Similarly, human GBM shows discordance between MMR gene mutations and TMB/MSI.Germline MMRd leads to promoted progression from low-grade to HGG and reduced survival compared to MMR-proficient (MMRp) tumor-bearing mice. This effect is not tumor cell intrinsic but is associated with MMRd in the tumor immune microenvironment, driving immunosuppressive myeloid programs, reduced lymphoid infiltration, and CD8+ T cell exhaustion. Both MMR-reduced (MMRr) and MMRd GBM are resistant to temozolomide (TMZ), unlike MMRp tumors. Our study shows that KL-50, a imidazotetrazine-based DNA targeting agent inducing MMR-independent cross-link–mediated cytotoxicity, was effective against germline and somatic MMRr/MMRd GBM, offering a potential therapy for TMZ-resistant HGG with MMR alterations.

Authors

Montserrat Puigdelloses Vallcorba, Nishant Soni, Seung-Won Choi, Kavita Rawat, Tanvi Joshi, Sam Friedman, Alice Buonfiglioli, Angelo Angione, Zhihong Chen, Gonzalo Piñero, Gabrielle Price, Mehek Dedhia, Raina Roche, Emir Radkevich, Anne M. Bowcock, Deepti Bhatt, Winfried Edelmann, Robert M. Samstein, Timothy E. Richardson, Nadejda M. Tsankova, Alexander M. Tsankov, Ranjit S. Bindra, Raul Rabadan, Juan C. Vasquez, Dolores Hambardzumyan