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 unco...
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| Veröffentlicht in: | Journal of cancer research and clinical oncology 2024-11, Vol.150 (11), p.496-496, Article 496 |
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| creator | Ibruli, Olta Rose, France Beleggia, Filippo Schmitt, Anna Cartolano, Maria Fernandez, Lucia Torres Saggau, Julia Bonasera, Debora Kiljan, Martha Gozum, Gokcen Lichius, Luca Cai, Jiali Niu, Li-na Caiaffa, Manoela Iannicelli Herter, Jan M. Walczak, Henning Liccardi, Gianmaria Grüll, Holger Büttner, Reinhard Bosco, Graziella George, Julie Thomas, Roman K. Bozek, Kasia Reinhardt, Hans Christian Herter-Sprie, Grit S. |
| description | 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. |
| doi_str_mv | 10.1007/s00432-024-05942-9 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11564195</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3128449016</sourcerecordid><originalsourceid>FETCH-LOGICAL-c345t-76aadbd64665a2934fcc1785cb33110b790114e86b7de967dc3b3c16cfeca7003</originalsourceid><addsrcrecordid>eNqNkk1v1DAQhiNERUvhD3BAlrhwCbXjr_iEqlX5kLaqxMfZcpzZXbeJHWxnpb3yy_F2S1s4IC72yPP49cz4rapXBL8jGMuzhDGjTY0bVmOuWFOrJ9UJ2R8RSvnTR_Fx9Tyla4yJ5LJ5Vh1TxVnTtuKk-nmOfNjCgMYwJyhrX-II1kwuz4PJzq9R3gC6vPxS97ACm90W0NfFcoHS3OXdBGj2tijEhIxHpuSDN90AKIFPrtAu71AOyI3j7AHZDdibKTifUTcEe2N6eFEdrcyQ4OXdflp9_3DxbfGpXl59_Lw4X9aWMp5rKYzpu14wIbhpFGUra4lsue0oJQR3UmFCGLSikz0oIXtLO2qJsKVoIzGmp9X7g-40dyP0FnyOZtBTdKOJOx2M039mvNvoddhqQrhgRPGi8PZOIYYfM6SsR5csDIPxUManKeGMSCWE_A-0zL9hslUFffMXeh3m6MsobinGSmOiUM2BsjGkFGF1XzjBem8HfbCDLnbQt3bQe-nXj1u-v_L7_wtAD0AqKb-G-PD2P2R_AVffwnU</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>3128449016</pqid></control><display><type>article</type><title>A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade</title><source>MEDLINE</source><source>DOAJ Directory of Open Access Journals</source><source>Springer Nature OA Free Journals</source><source>Springer Nature - Complete Springer Journals</source><creator>Ibruli, Olta ; Rose, France ; Beleggia, Filippo ; Schmitt, Anna ; Cartolano, Maria ; Fernandez, Lucia Torres ; Saggau, Julia ; Bonasera, Debora ; Kiljan, Martha ; Gozum, Gokcen ; Lichius, Luca ; Cai, Jiali ; Niu, Li-na ; Caiaffa, Manoela Iannicelli ; Herter, Jan M. ; Walczak, Henning ; Liccardi, Gianmaria ; Grüll, Holger ; Büttner, Reinhard ; Bosco, Graziella ; George, Julie ; Thomas, Roman K. ; Bozek, Kasia ; Reinhardt, Hans Christian ; Herter-Sprie, Grit S.</creator><creatorcontrib>Ibruli, Olta ; Rose, France ; Beleggia, Filippo ; Schmitt, Anna ; Cartolano, Maria ; Fernandez, Lucia Torres ; Saggau, Julia ; Bonasera, Debora ; Kiljan, Martha ; Gozum, Gokcen ; Lichius, Luca ; Cai, Jiali ; Niu, Li-na ; Caiaffa, Manoela Iannicelli ; Herter, Jan M. ; Walczak, Henning ; Liccardi, Gianmaria ; Grüll, Holger ; Büttner, Reinhard ; Bosco, Graziella ; George, Julie ; Thomas, Roman K. ; Bozek, Kasia ; Reinhardt, Hans Christian ; Herter-Sprie, Grit S.</creatorcontrib><description>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.</description><identifier>ISSN: 1432-1335</identifier><identifier>ISSN: 0171-5216</identifier><identifier>EISSN: 1432-1335</identifier><identifier>DOI: 10.1007/s00432-024-05942-9</identifier><identifier>PMID: 39542886</identifier><language>eng</language><publisher>Berlin/Heidelberg: Springer Berlin Heidelberg</publisher><subject>Animals ; Cancer Research ; Cell survival ; Chemotherapy ; death ; Disease Models, Animal ; DNA Mismatch Repair ; DNA repair ; drug therapy ; genes ; Genetic engineering ; Genomics ; Hematology ; Humans ; Immune checkpoint inhibitors ; Immune Checkpoint Inhibitors - pharmacology ; Immune Checkpoint Inhibitors - therapeutic use ; Immunogenicity ; Immunotherapy ; Internal Medicine ; lung neoplasms ; Lung Neoplasms - drug therapy ; Lung Neoplasms - genetics ; Lung Neoplasms - immunology ; Lung Neoplasms - pathology ; Medical prognosis ; Medicine ; Medicine & Public Health ; Mice ; Mismatch repair ; MSH2 protein ; MutS Homolog 2 Protein - genetics ; Neoantigens ; Oncology ; prognosis ; relapse ; Small cell lung carcinoma ; 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 ; Tumors ; Whole genome sequencing</subject><ispartof>Journal of cancer research and clinical oncology, 2024-11, Vol.150 (11), p.496-496, Article 496</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>The Author(s) 2024 2024</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c345t-76aadbd64665a2934fcc1785cb33110b790114e86b7de967dc3b3c16cfeca7003</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1007/s00432-024-05942-9$$EPDF$$P50$$Gspringer$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1007/s00432-024-05942-9$$EHTML$$P50$$Gspringer$$Hfree_for_read</linktohtml><link.rule.ids>230,314,777,781,861,882,27905,27906,41101,41469,42170,42538,51300,51557</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39542886$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ibruli, Olta</creatorcontrib><creatorcontrib>Rose, France</creatorcontrib><creatorcontrib>Beleggia, Filippo</creatorcontrib><creatorcontrib>Schmitt, Anna</creatorcontrib><creatorcontrib>Cartolano, Maria</creatorcontrib><creatorcontrib>Fernandez, Lucia Torres</creatorcontrib><creatorcontrib>Saggau, Julia</creatorcontrib><creatorcontrib>Bonasera, Debora</creatorcontrib><creatorcontrib>Kiljan, Martha</creatorcontrib><creatorcontrib>Gozum, Gokcen</creatorcontrib><creatorcontrib>Lichius, Luca</creatorcontrib><creatorcontrib>Cai, Jiali</creatorcontrib><creatorcontrib>Niu, Li-na</creatorcontrib><creatorcontrib>Caiaffa, Manoela Iannicelli</creatorcontrib><creatorcontrib>Herter, Jan M.</creatorcontrib><creatorcontrib>Walczak, Henning</creatorcontrib><creatorcontrib>Liccardi, Gianmaria</creatorcontrib><creatorcontrib>Grüll, Holger</creatorcontrib><creatorcontrib>Büttner, Reinhard</creatorcontrib><creatorcontrib>Bosco, Graziella</creatorcontrib><creatorcontrib>George, Julie</creatorcontrib><creatorcontrib>Thomas, Roman K.</creatorcontrib><creatorcontrib>Bozek, Kasia</creatorcontrib><creatorcontrib>Reinhardt, Hans Christian</creatorcontrib><creatorcontrib>Herter-Sprie, Grit S.</creatorcontrib><title>A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade</title><title>Journal of cancer research and clinical oncology</title><addtitle>J Cancer Res Clin Oncol</addtitle><addtitle>J Cancer Res Clin Oncol</addtitle><description>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.</description><subject>Animals</subject><subject>Cancer Research</subject><subject>Cell survival</subject><subject>Chemotherapy</subject><subject>death</subject><subject>Disease Models, Animal</subject><subject>DNA Mismatch Repair</subject><subject>DNA repair</subject><subject>drug therapy</subject><subject>genes</subject><subject>Genetic engineering</subject><subject>Genomics</subject><subject>Hematology</subject><subject>Humans</subject><subject>Immune checkpoint inhibitors</subject><subject>Immune Checkpoint Inhibitors - pharmacology</subject><subject>Immune Checkpoint Inhibitors - therapeutic use</subject><subject>Immunogenicity</subject><subject>Immunotherapy</subject><subject>Internal Medicine</subject><subject>lung neoplasms</subject><subject>Lung Neoplasms - drug therapy</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - immunology</subject><subject>Lung Neoplasms - pathology</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Mice</subject><subject>Mismatch repair</subject><subject>MSH2 protein</subject><subject>MutS Homolog 2 Protein - genetics</subject><subject>Neoantigens</subject><subject>Oncology</subject><subject>prognosis</subject><subject>relapse</subject><subject>Small cell lung carcinoma</subject><subject>Small Cell Lung Carcinoma - drug therapy</subject><subject>Small Cell Lung Carcinoma - genetics</subject><subject>Small Cell Lung Carcinoma - immunology</subject><subject>Small Cell Lung Carcinoma - pathology</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumors</subject><subject>Whole genome sequencing</subject><issn>1432-1335</issn><issn>0171-5216</issn><issn>1432-1335</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNqNkk1v1DAQhiNERUvhD3BAlrhwCbXjr_iEqlX5kLaqxMfZcpzZXbeJHWxnpb3yy_F2S1s4IC72yPP49cz4rapXBL8jGMuzhDGjTY0bVmOuWFOrJ9UJ2R8RSvnTR_Fx9Tyla4yJ5LJ5Vh1TxVnTtuKk-nmOfNjCgMYwJyhrX-II1kwuz4PJzq9R3gC6vPxS97ACm90W0NfFcoHS3OXdBGj2tijEhIxHpuSDN90AKIFPrtAu71AOyI3j7AHZDdibKTifUTcEe2N6eFEdrcyQ4OXdflp9_3DxbfGpXl59_Lw4X9aWMp5rKYzpu14wIbhpFGUra4lsue0oJQR3UmFCGLSikz0oIXtLO2qJsKVoIzGmp9X7g-40dyP0FnyOZtBTdKOJOx2M039mvNvoddhqQrhgRPGi8PZOIYYfM6SsR5csDIPxUManKeGMSCWE_A-0zL9hslUFffMXeh3m6MsobinGSmOiUM2BsjGkFGF1XzjBem8HfbCDLnbQt3bQe-nXj1u-v_L7_wtAD0AqKb-G-PD2P2R_AVffwnU</recordid><startdate>20241114</startdate><enddate>20241114</enddate><creator>Ibruli, Olta</creator><creator>Rose, France</creator><creator>Beleggia, Filippo</creator><creator>Schmitt, Anna</creator><creator>Cartolano, Maria</creator><creator>Fernandez, Lucia Torres</creator><creator>Saggau, Julia</creator><creator>Bonasera, Debora</creator><creator>Kiljan, Martha</creator><creator>Gozum, Gokcen</creator><creator>Lichius, Luca</creator><creator>Cai, Jiali</creator><creator>Niu, Li-na</creator><creator>Caiaffa, Manoela Iannicelli</creator><creator>Herter, Jan M.</creator><creator>Walczak, Henning</creator><creator>Liccardi, Gianmaria</creator><creator>Grüll, Holger</creator><creator>Büttner, Reinhard</creator><creator>Bosco, Graziella</creator><creator>George, Julie</creator><creator>Thomas, Roman K.</creator><creator>Bozek, Kasia</creator><creator>Reinhardt, Hans Christian</creator><creator>Herter-Sprie, Grit S.</creator><general>Springer Berlin Heidelberg</general><general>Springer Nature B.V</general><scope>C6C</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TO</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20241114</creationdate><title>A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade</title><author>Ibruli, Olta ; Rose, France ; Beleggia, Filippo ; Schmitt, Anna ; Cartolano, Maria ; Fernandez, Lucia Torres ; Saggau, Julia ; Bonasera, Debora ; Kiljan, Martha ; Gozum, Gokcen ; Lichius, Luca ; Cai, Jiali ; Niu, Li-na ; Caiaffa, Manoela Iannicelli ; Herter, Jan M. ; Walczak, Henning ; Liccardi, Gianmaria ; Grüll, Holger ; Büttner, Reinhard ; Bosco, Graziella ; George, Julie ; Thomas, Roman K. ; Bozek, Kasia ; Reinhardt, Hans Christian ; Herter-Sprie, Grit S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c345t-76aadbd64665a2934fcc1785cb33110b790114e86b7de967dc3b3c16cfeca7003</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Cancer Research</topic><topic>Cell survival</topic><topic>Chemotherapy</topic><topic>death</topic><topic>Disease Models, Animal</topic><topic>DNA Mismatch Repair</topic><topic>DNA repair</topic><topic>drug therapy</topic><topic>genes</topic><topic>Genetic engineering</topic><topic>Genomics</topic><topic>Hematology</topic><topic>Humans</topic><topic>Immune checkpoint inhibitors</topic><topic>Immune Checkpoint Inhibitors - pharmacology</topic><topic>Immune Checkpoint Inhibitors - therapeutic use</topic><topic>Immunogenicity</topic><topic>Immunotherapy</topic><topic>Internal Medicine</topic><topic>lung neoplasms</topic><topic>Lung Neoplasms - drug therapy</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - immunology</topic><topic>Lung Neoplasms - pathology</topic><topic>Medical prognosis</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Mice</topic><topic>Mismatch repair</topic><topic>MSH2 protein</topic><topic>MutS Homolog 2 Protein - genetics</topic><topic>Neoantigens</topic><topic>Oncology</topic><topic>prognosis</topic><topic>relapse</topic><topic>Small cell lung carcinoma</topic><topic>Small Cell Lung Carcinoma - drug therapy</topic><topic>Small Cell Lung Carcinoma - genetics</topic><topic>Small Cell Lung Carcinoma - immunology</topic><topic>Small Cell Lung Carcinoma - pathology</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumors</topic><topic>Whole genome sequencing</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Ibruli, Olta</creatorcontrib><creatorcontrib>Rose, France</creatorcontrib><creatorcontrib>Beleggia, Filippo</creatorcontrib><creatorcontrib>Schmitt, Anna</creatorcontrib><creatorcontrib>Cartolano, Maria</creatorcontrib><creatorcontrib>Fernandez, Lucia Torres</creatorcontrib><creatorcontrib>Saggau, Julia</creatorcontrib><creatorcontrib>Bonasera, Debora</creatorcontrib><creatorcontrib>Kiljan, Martha</creatorcontrib><creatorcontrib>Gozum, Gokcen</creatorcontrib><creatorcontrib>Lichius, Luca</creatorcontrib><creatorcontrib>Cai, Jiali</creatorcontrib><creatorcontrib>Niu, Li-na</creatorcontrib><creatorcontrib>Caiaffa, Manoela Iannicelli</creatorcontrib><creatorcontrib>Herter, Jan M.</creatorcontrib><creatorcontrib>Walczak, Henning</creatorcontrib><creatorcontrib>Liccardi, Gianmaria</creatorcontrib><creatorcontrib>Grüll, Holger</creatorcontrib><creatorcontrib>Büttner, Reinhard</creatorcontrib><creatorcontrib>Bosco, Graziella</creatorcontrib><creatorcontrib>George, Julie</creatorcontrib><creatorcontrib>Thomas, Roman K.</creatorcontrib><creatorcontrib>Bozek, Kasia</creatorcontrib><creatorcontrib>Reinhardt, Hans Christian</creatorcontrib><creatorcontrib>Herter-Sprie, Grit S.</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><collection>AGRICOLA</collection><collection>AGRICOLA - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Journal of cancer research and clinical oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Ibruli, Olta</au><au>Rose, France</au><au>Beleggia, Filippo</au><au>Schmitt, Anna</au><au>Cartolano, Maria</au><au>Fernandez, Lucia Torres</au><au>Saggau, Julia</au><au>Bonasera, Debora</au><au>Kiljan, Martha</au><au>Gozum, Gokcen</au><au>Lichius, Luca</au><au>Cai, Jiali</au><au>Niu, Li-na</au><au>Caiaffa, Manoela Iannicelli</au><au>Herter, Jan M.</au><au>Walczak, Henning</au><au>Liccardi, Gianmaria</au><au>Grüll, Holger</au><au>Büttner, Reinhard</au><au>Bosco, Graziella</au><au>George, Julie</au><au>Thomas, Roman K.</au><au>Bozek, Kasia</au><au>Reinhardt, Hans Christian</au><au>Herter-Sprie, Grit S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade</atitle><jtitle>Journal of cancer research and clinical oncology</jtitle><stitle>J Cancer Res Clin Oncol</stitle><addtitle>J Cancer Res Clin Oncol</addtitle><date>2024-11-14</date><risdate>2024</risdate><volume>150</volume><issue>11</issue><spage>496</spage><epage>496</epage><pages>496-496</pages><artnum>496</artnum><issn>1432-1335</issn><issn>0171-5216</issn><eissn>1432-1335</eissn><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.</abstract><cop>Berlin/Heidelberg</cop><pub>Springer Berlin Heidelberg</pub><pmid>39542886</pmid><doi>10.1007/s00432-024-05942-9</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1432-1335 |
| ispartof | Journal of cancer research and clinical oncology, 2024-11, Vol.150 (11), p.496-496, Article 496 |
| issn | 1432-1335 0171-5216 1432-1335 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_11564195 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Springer Nature OA Free Journals; Springer Nature - Complete Springer Journals |
| subjects | Animals Cancer Research Cell survival Chemotherapy death Disease Models, Animal DNA Mismatch Repair DNA repair drug therapy genes Genetic engineering Genomics Hematology Humans Immune checkpoint inhibitors Immune Checkpoint Inhibitors - pharmacology Immune Checkpoint Inhibitors - therapeutic use Immunogenicity Immunotherapy Internal Medicine lung neoplasms Lung Neoplasms - drug therapy Lung Neoplasms - genetics Lung Neoplasms - immunology Lung Neoplasms - pathology Medical prognosis Medicine Medicine & Public Health Mice Mismatch repair MSH2 protein MutS Homolog 2 Protein - genetics Neoantigens Oncology prognosis relapse Small cell lung carcinoma 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 Tumors Whole genome sequencing |
| title | A novel mouse model recapitulating the MMR-defective SCLC subtype uncovers an actionable sensitivity to immune checkpoint blockade |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-20T02%3A03%3A46IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=A%20novel%20mouse%20model%20recapitulating%20the%20MMR-defective%20SCLC%20subtype%20uncovers%20an%20actionable%20sensitivity%20to%20immune%20checkpoint%20blockade&rft.jtitle=Journal%20of%20cancer%20research%20and%20clinical%20oncology&rft.au=Ibruli,%20Olta&rft.date=2024-11-14&rft.volume=150&rft.issue=11&rft.spage=496&rft.epage=496&rft.pages=496-496&rft.artnum=496&rft.issn=1432-1335&rft.eissn=1432-1335&rft_id=info:doi/10.1007/s00432-024-05942-9&rft_dat=%3Cproquest_pubme%3E3128449016%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=3128449016&rft_id=info:pmid/39542886&rfr_iscdi=true |