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
{"title":"再现 MMR 缺陷 SCLC 亚型的新型小鼠模型发现了对免疫检查点阻断剂的可操作性敏感性。","authors":"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","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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<sup>fl/fl</sup>;Trp53<sup>fl/fl</sup> (RP) model. Genomic characteristics and preclinical therapy responses were evaluated by focusing on overall survival and whole exome sequencing (WES) analyses.</p><p><strong>Results: </strong>MMR-defective SCLC tumors (Rb1<sup>fl/fl</sup>;Trp53<sup>fl/fl</sup>;Msh2<sup>fl/fl</sup> (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.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":15118,"journal":{"name":"Journal of Cancer Research and Clinical Oncology","volume":"150 11","pages":"496"},"PeriodicalIF":2.7000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564195/pdf/","citationCount":"0","resultStr":"{\"title\":\"A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade.\",\"authors\":\"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\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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<sup>fl/fl</sup>;Trp53<sup>fl/fl</sup> (RP) model. Genomic characteristics and preclinical therapy responses were evaluated by focusing on overall survival and whole exome sequencing (WES) analyses.</p><p><strong>Results: </strong>MMR-defective SCLC tumors (Rb1<sup>fl/fl</sup>;Trp53<sup>fl/fl</sup>;Msh2<sup>fl/fl</sup> (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.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":15118,\"journal\":{\"name\":\"Journal of Cancer Research and Clinical Oncology\",\"volume\":\"150 11\",\"pages\":\"496\"},\"PeriodicalIF\":2.7000,\"publicationDate\":\"2024-11-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11564195/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Cancer Research and Clinical Oncology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00432-024-05942-9\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Cancer Research and Clinical Oncology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00432-024-05942-9","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"ONCOLOGY","Score":null,"Total":0}
A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade.
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.
期刊介绍：
The "Journal of Cancer Research and Clinical Oncology" publishes significant and up-to-date articles within the fields of experimental and clinical oncology. The journal, which is chiefly devoted to Original papers, also includes Reviews as well as Editorials and Guest editorials on current, controversial topics. The section Letters to the editors provides a forum for a rapid exchange of comments and information concerning previously published papers and topics of current interest. Meeting reports provide current information on the latest results presented at important congresses.
The following fields are covered: carcinogenesis - etiology, mechanisms; molecular biology; recent developments in tumor therapy; general diagnosis; laboratory diagnosis; diagnostic and experimental pathology; oncologic surgery; and epidemiology.
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