A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade

Olta Ibruli; France Rose; Filippo Beleggia; Anna Schmitt; Maria Cartolano; Lucia Torres Fernandez; Julia Saggau; Debora Bonasera; Martha Kiljan; Gokcen Gozum; Luca Lichius; Jiali Cai; Li-Na Niu; Manoela Iannicelli Caiaffa; Jan M Herter; Henning Walczak; Gianmaria Liccardi; Holger Grüll; Reinhard Büttner; Graziella Bosco; Julie George; Roman K Thomas; Kasia Bozek; Hans Christian Reinhardt; Grit S Herter-Sprie

doi:10.1007/s00432-024-05942-9

A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade

J Cancer Res Clin Oncol. 2024 Nov 14;150(11):496. doi: 10.1007/s00432-024-05942-9.

Authors

Olta Ibruli^#^{1

2}, France Rose^#^{3

4}, Filippo Beleggia^{1

2

5}, Anna Schmitt^{2

6}, Maria Cartolano^{1

3}, Lucia Torres Fernandez¹, Julia Saggau^{3

7}, Debora Bonasera^{3

7}, Martha Kiljan^{2

3}, Gokcen Gozum^{2

3}, Luca Lichius⁸, Jiali Cai^{3

9}, Li-Na Niu^{3

9}, Manoela Iannicelli Caiaffa^{1

2

5}, Jan M Herter^{3

9

10}, Henning Walczak^{7

11

12}, Gianmaria Liccardi^{3

7}, Holger Grüll¹³, Reinhard Büttner¹⁴, Graziella Bosco¹, Julie George^{1

15}, Roman K Thomas^{1

14}, Kasia Bozek^#^{3

4}, Hans Christian Reinhardt^#^{16

17

18

19}, Grit S Herter-Sprie^#^{20

21

22}

Affiliations

¹ Department of Translational Genomics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
² Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁴ Institute for Biomedical Informatics, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵ Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶ Institute of Virology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁷ Institute of Biochemistry I, Center for Biochemistry, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁸ Department II of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
⁹ Department of Radiation Oncology and Cyberknife Center, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.
¹⁰ Department of Radiation Oncology, MVZ Prof. Dr. Uhlenbrock und Partner, Gesundheitscampus Josephs-Hospital, Warendorf, Germany.
¹¹ Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
¹² Center for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
¹³ Institute for Diagnostic and Interventional Radiology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁴ Institute of Pathology, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁵ Department of Otorhinolaryngology, Faculty of Medicine, University Hospital of Cologne, University of Cologne, Cologne, Germany.
¹⁶ Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany.
¹⁷ West German Cancer Center, University Hospital Essen, Essen, Germany.
¹⁸ DKTK Partner Site Essen/Düsseldorf, University Hospital Essen, Essen, Germany.
¹⁹ Center for Molecular Biotechnology, University Hospital Essen, Essen, Germany.
²⁰ Department I of Internal Medicine, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany. [email protected].
²¹ Center for Molecular Medicine Cologne, Faculty of Medicine, University Hospital Cologne, University of Cologne, Cologne, Germany. [email protected].
²² Department of Medical Oncology, Fachklinik Hornheide, Münster, Germany. [email protected].

^# Contributed equally.

Abstract

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 Rb1^fl/fl;Trp53^fl/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 (Rb1^fl/fl;Trp53^fl/fl;Msh2^fl/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.

Keywords: Genetically engineered mouse model; Immune checkpoint inhibitor; Mismatch repair deficiency; Small cell lung cancer; Tumor mutational burden.

MeSH terms

Animals
DNA Mismatch Repair*
Disease Models, Animal*
Humans
Immune Checkpoint Inhibitors* / pharmacology
Immune Checkpoint Inhibitors* / therapeutic use
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / immunology
Lung Neoplasms* / pathology
Mice
MutS Homolog 2 Protein* / genetics
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / genetics
Small Cell Lung Carcinoma* / immunology
Small Cell Lung Carcinoma* / pathology
Tumor Suppressor Protein p53 / genetics

Substances

Immune Checkpoint Inhibitors
MutS Homolog 2 Protein
Msh2 protein, mouse
Tumor Suppressor Protein p53

Abstract

MeSH terms

Substances

Grants and funding