Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models
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 (HGGs), including glioblastomas (GBMs). However, the specific roles of individual MMR genes in the initiation, progression, TMB, microsatellite instability (MSI), and resistance to TMZ in gliomas remain unclear. Here, we developed de novo mouse models of germline and somatic MMR-deficient (MMRd) HGGs. Surprisingly, loss of Msh2 or Msh6 did not lead to high TMB, MSI, nor did it confer a response to anti-programmed cell death 1 (anti-PD-1) in GBM. Similarly, human GBM showed discordance between MMR gene mutations and the TMB and MSI. Germline MMRd promoted the progression from low-grade to HGG and reduced survival compared with MMR-proficient (MMRp) tumor-bearing mice. This effect was not tumor cell intrinsic but was 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 were resistant to TMZ, unlike MMRp tumors. Our study shows that N3-(2-fluoroethyl) imidazotetrazine (KL-50), an imidazotetrazine-based DNA targeting agent that induces MMR-independent cross-link-mediated cytotoxicity, was effective against germline and somatic MMRr and MMRd GBMs, offering a potential therapy for TMZ-resistant HGG with MMR alterations.
Authors
- Gonzalo Piñero (ORCID: https://orcid.org/0000-0001-8510-9598)
- A. Bowcock (ORCID: https://orcid.org/0000-0001-8691-9090)
- Alice Buonfiglioli (ORCID: https://orcid.org/0000-0002-5550-9360)
- Seung-Won Choi (ORCID: https://orcid.org/0000-0001-8610-887X)
- Sam Friedman (ORCID: https://orcid.org/0000-0003-1686-2791)
- R Rodríguez Roche
- Ranjit S. Bindra (ORCID: https://orcid.org/0000-0002-3255-0467)
- Nadejda M. Tsankova (ORCID: https://orcid.org/0000-0002-5333-312X)
- Dolores Hambardzumyan
- Timothy E. Richardson (ORCID: https://orcid.org/0000-0001-7068-5517)
- Robert Samstein (ORCID: https://orcid.org/0000-0001-6860-2401)
- Nishant Soni (ORCID: https://orcid.org/0000-0003-1567-0712)
- Angelo Angione (ORCID: https://orcid.org/0000-0001-7713-5833)
- Deepti Bhatt (ORCID: https://orcid.org/0000-0002-4904-4886)
- Alexander M. Tsankov (ORCID: https://orcid.org/0000-0002-7955-4414)
- Kavita Rawat (ORCID: https://orcid.org/0000-0002-8302-9890)
- Raul Rabadan
- Emir Radkevich
- Gabrielle A. Price (ORCID: https://orcid.org/0000-0001-6054-2395)
- Winfried Edelmann
- Juan C. Vasquez
- Zhihong Chen
- Montserrat Puigdelloses Vallcorba
- Mehek Dedhia
- Tanvi Joshi
Institutions
- Albert Einstein College of Medicine (US)
- Cancer Institute (WIA) (IN)
- Yale University (US)
- Tisch Hospital (US)
- Guangdong Province Environmental Monitoring Center (CN)
- Tisch Cancer Institute
- Columbia University (US)
- University of Pennsylvania (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-12-23
- DOI
- https://doi.org/10.1172/jci195189
- Citations
- 1
- Primary Topic
- Glioma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- American Association for Cancer Research
- Yale University
- Icahn School of Medicine at Mount Sinai
- Ian's Friends Foundation
- National Institutes of Health
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- Hyundai Hope On Wheels