Universität zu Köln

Ibruli, Olta, Rose, France ORCID: 0000-0001-5828-3259, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Schmitt, Anna ORCID: 0009-0002-7655-1805, Cartolano, Maria ORCID: 0000-0002-2444-6950, Fernandez, Lucia Torres ORCID: 0000-0002-8890-6258, Saggau, Julia ORCID: 0000-0002-9908-5467, Bonasera, Debora ORCID: 0000-0003-1567-2283, Kiljan, Martha ORCID: 0000-0002-5581-1359, Gozum, Gokcen ORCID: 0000-0002-8650-0078, Lichius, Luca, Cai, Jiali ORCID: 0009-0009-5976-0235, Niu, Li-na ORCID: 0000-0002-6653-0819, Caiaffa, Manoela Iannicelli ORCID: 0009-0007-0704-0397, Herter, Jan M., Walczak, Henning ORCID: 0000-0002-6312-4591, Liccardi, Gianmaria ORCID: 0000-0002-2662-1281, Grüll, Holger ORCID: 0000-0002-0993-9300, Büttner, Reinhard ORCID: 0000-0001-8806-4786, Bosco, Graziella ORCID: 0000-0001-6601-4518, George, Julie ORCID: 0000-0002-4272-3683, Thomas, Roman K. ORCID: 0000-0001-9132-4876, Bozek, Kasia ORCID: 0000-0002-0917-6876, Reinhardt, Hans Christian and Herter-Sprie, Grit S. ORCID: 0000-0002-1910-9415 (2024). A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade. Journal of Cancer Research and Clinical Oncology, 150 (11). pp. 1-13. Springer Nature. ISSN 1432-1335

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Abstract

[Artikel-Nr.: 496] 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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Ibruli, Olta UNSPECIFIED UNSPECIFIED UNSPECIFIED Rose, France UNSPECIFIED https://orcid.org/0000-0001-5828-3259 UNSPECIFIED Beleggia, Filippo UNSPECIFIED https://orcid.org/0000-0003-0234-7094 UNSPECIFIED Schmitt, Anna UNSPECIFIED https://orcid.org/0009-0002-7655-1805 UNSPECIFIED Cartolano, Maria UNSPECIFIED https://orcid.org/0000-0002-2444-6950 UNSPECIFIED Fernandez, Lucia Torres UNSPECIFIED https://orcid.org/0000-0002-8890-6258 UNSPECIFIED Saggau, Julia UNSPECIFIED https://orcid.org/0000-0002-9908-5467 UNSPECIFIED Bonasera, Debora UNSPECIFIED https://orcid.org/0000-0003-1567-2283 UNSPECIFIED Kiljan, Martha UNSPECIFIED https://orcid.org/0000-0002-5581-1359 UNSPECIFIED Gozum, Gokcen UNSPECIFIED https://orcid.org/0000-0002-8650-0078 UNSPECIFIED Lichius, Luca UNSPECIFIED UNSPECIFIED UNSPECIFIED Cai, Jiali UNSPECIFIED https://orcid.org/0009-0009-5976-0235 UNSPECIFIED Niu, Li-na UNSPECIFIED https://orcid.org/0000-0002-6653-0819 UNSPECIFIED Caiaffa, Manoela Iannicelli UNSPECIFIED https://orcid.org/0009-0007-0704-0397 UNSPECIFIED Herter, Jan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Walczak, Henning UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Liccardi, Gianmaria UNSPECIFIED https://orcid.org/0000-0002-2662-1281 UNSPECIFIED Grüll, Holger UNSPECIFIED https://orcid.org/0000-0002-0993-9300 UNSPECIFIED Büttner, Reinhard UNSPECIFIED https://orcid.org/0000-0001-8806-4786 UNSPECIFIED Bosco, Graziella UNSPECIFIED https://orcid.org/0000-0001-6601-4518 UNSPECIFIED George, Julie UNSPECIFIED https://orcid.org/0000-0002-4272-3683 UNSPECIFIED Thomas, Roman K. UNSPECIFIED https://orcid.org/0000-0001-9132-4876 UNSPECIFIED Bozek, Kasia UNSPECIFIED https://orcid.org/0000-0002-0917-6876 UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Herter-Sprie, Grit S. UNSPECIFIED https://orcid.org/0000-0002-1910-9415 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815990
Identification Number:	10.1007/s00432-024-05942-9
Journal or Publication Title:	Journal of Cancer Research and Clinical Oncology
Volume:	150
Number:	11
Page Range:	pp. 1-13
Date:	14 November 2024
Publisher:	Springer Nature
ISSN:	1432-1335
Language:	English
Faculty:	Faculty of Medicine Central Institutions / Interdisciplinary Research Centers
Divisions:	Faculty of Medicine > Biochemie > Institut I für Biochemie Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Innere Medizin > Klinik II für Innere Medizin - Nephrologie, Rheumatologie, Diabetologie und Allgemeine Innere Medizin Faculty of Medicine > Strahlentherapie > Klinik und Poliklinik für Radioonkologie, Cyberknife- und Strahlentherapie Faculty of Medicine > Virologie > Institut für Virologie Faculty of Medicine > Weitere > Institut für Biomedizinische Informatik Faculty of Medicine > Weitere > Translationale Genomik Zentrum für Molekulare Medizin CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Hals-Nasen-Ohrenheilkunde > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde Faculty of Medicine > Radiologische Diagnostik > Institut und Poliklinik für Radiologische Diagnostik
Subjects:	Life sciences Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Small cell lung cancer ; Immune checkpoint inhibitor ; Tumor mutational burden ; Mismatch repair deficiency ; Genetically engineered mouse model English
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81599