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A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune
Olta Ibruli1,2, France Rose3,4, Filippo Beleggia1,2,5
1Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
Purpose:
Small cell lung cancer (SCLC) has an extremely poor prognosis. Despite high initial response rates to chemotherapy and modest survival improvements with the addition of immune checkpoint inhibitors (ICI), almost all patients experience relapse and fatal outcomes. Recent genomic insights uncovered extensive molecular heterogeneity in addition to the almost uniform loss of RB1 and TRP53. Additionally, defective DNA mismatch repair (MMR) has recently been described in some SCLC cases. Here, we generated a novel SCLC mouse model capturing MMR deficiency and assessed immunotherapy responses.
Methods:
We developed an MMR-deficient genetically engineered mouse model (GEMM) of SCLC by introducing a conditional Msh2 gene, crucial for maintaining MMR integrity, into the standard Rb1fl/fl;Trp53fl/fl (RP) model. Genomic characteristics and preclinical therapy responses were evaluated by focusing on overall survival and whole exome sequencing (WES) analyses.
Results:
MMR-defective SCLC tumors (Rb1fl/fl;Trp53fl/fl;Msh2fl/fl (RPM)) developed later than tumors in MMR-proficient mice. However, the time from tumor manifestation to death of the affected animals was substantially shortened (median survival 55 days in RP vs. 46.5 days in RPM), indicating increased aggressiveness of MMR-defective tumors. RPM tumors exhibited MMR deficiency, high tumor mutational burden (TMB), and an elevated load of candidate neoantigens, compared to RP lesions (p = 0.0106), suggesting increased immunogenicity. Importantly, the overall survival of RPM animals was significantly improved when exposed to ICI.
Conclusion:
We propose a novel RPM mouse model as a suitable system to mimic MMR-defective SCLC and tumors with high TMB. We provide in vivo evidence that Msh2 deficiency enhances ICI sensitivity. These findings could contribute to stratifying SCLC patients to immunotherapy, thereby improving treatment outcomes.
Insights
Small cell lung cancer (SCLC) with defective DNA mismatch repair (MMR) shows increased aggressiveness but responds better to immune checkpoint inhibitors (ICI). This novel mouse model aids in understanding and treating MMR-deficient SCLC.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Small cell lung cancer (SCLC) has a poor prognosis despite current treatments.
- Immune checkpoint inhibitors (ICI) offer modest survival benefits but relapse is common.
- Defective DNA mismatch repair (MMR) is a newly identified characteristic in some SCLC cases.
Purpose of the Study:
- To develop and characterize a novel mouse model of MMR-deficient SCLC.
- To assess the impact of MMR deficiency on tumor aggressiveness and immunogenicity.
- To evaluate the response of MMR-deficient SCLC to immunotherapy.
Main Methods:
- A genetically engineered mouse model (GEMM) of SCLC was created by incorporating a conditional Msh2 gene into the Rb1fl/fl;Trp53fl/fl (RP) model, creating the RPM model.
- Genomic characteristics were analyzed using whole exome sequencing (WES).
- Therapeutic responses were evaluated focusing on overall survival and tumor characteristics.
Main Results:
- MMR-defective SCLC tumors (RPM) developed later but showed increased aggressiveness, with shorter survival times compared to MMR-proficient tumors (RP).
- RPM tumors exhibited higher tumor mutational burden (TMB) and neoantigen load, suggesting increased immunogenicity.
- MMR-defective SCLC (RPM) demonstrated significantly improved overall survival when treated with ICI.
Conclusions:
- A novel mouse model (RPM) effectively mimics MMR-defective SCLC with high TMB.
- Msh2 deficiency enhances sensitivity to ICI in SCLC.
- These findings support patient stratification for immunotherapy to improve SCLC treatment outcomes.
