Mismatch repair deficiency drives malignant progression and alters the tumor immune microenvironment in glioblastoma models
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
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
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Research Article Cell biology Immunology Neuroscience Oncology

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

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 (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

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

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Figure 7

Germline MMRr, MMRd, and somatic MMRd confer resistance to TMZ in vivo.

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Germline MMRr, MMRd, and somatic MMRd confer resistance to TMZ in vivo. ...
(A) Schematic illustration of the experimental steps for TMZ treatment. (B) Survival curves of tumor-bearing mice treated with VEH or TMZ. (C) Schematic illustration of the experimental steps for TMZ treatment and the time points for blood and tumor collection. (D and E) Heatmap quantifications of spectral flow cytometry myeloid and lymphoid panels in the blood at days 0 and 7 (D) and tumors at the survival endpoint (E). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by MC and GBW test (B), paired t test (D), and unpaired t test (E).