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 8

KL-50 treatment is potent against MMRp tumors as well as germline and somatic MMRd tumors.

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KL-50 treatment is potent against MMRp tumors as well as germline and so...
(A) Schematic illustration of experimental steps for KL-50 treatment in WT and somatic MMRd tumor–bearing mice and in WT and germline MMRd tumor–bearing mice. (B) Survival curves for WT and somatic MMRd tumor–bearing mice treated with VEH or KL-50. (C) Survival curves for WT and Msh2 heterozygous tumor–bearing mice treated with VEH or KL-50. (D) Schematic illustration of experimental steps for KL-50 treatment and time points of blood and heatmap quantifications of spectral flow cytometry myeloid and lymphoid panels in the blood at treatment days 0 and 12 and tumors at day 12 (48 hours after the last dose). (E) Schematic illustration of the experimental steps for KL-50 treatment and the time point of tumor collection, along with heatmap quantifications of spectral flow cytometry myeloid and lymphoid panels. (F) Schematic illustration of the experimental steps for MRI-based assessment of KL-50 efficacy in germline MMRd tumor–bearing mice. Illustration created with BioRender. (G) Initial MRI volumes were equally distributed in the VEH and KL-50 treatment groups in WT and germline MMRd tumors. (H) Ratio of tumor volume on day 6 after treatment over initial pretreatment volumes. (I) Representative MRI images of WT and germline MMRd tumor–bearing mice at day 0 and day 6 after VEH or KL-50 treatment. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by MC and GBW test (B) and paired t-test (D) and unpaired t-test (E and H). Data are presented as the mean ± standard deviation.