BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors
Background Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4)...
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BMJ Publishing Group
2023-04-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/4/e006070.full |
| _version_ | 1797844198016155648 |
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| author | Li Zhang Xi Li Gang Chen Yu Fu Bin Yang Wenting Li Jingbo Liu Xu Qin Gordon B Mills Yaoyuan Cui Xingyuan Hu Funian Lu Tianyu Qin Zhe Hu Ensong Guo Junpeng Fan Rourou Xiao Dianxing Hu Wenju Peng Beibei Wang Chaoyang Sun |
| author_facet | Li Zhang Xi Li Gang Chen Yu Fu Bin Yang Wenting Li Jingbo Liu Xu Qin Gordon B Mills Yaoyuan Cui Xingyuan Hu Funian Lu Tianyu Qin Zhe Hu Ensong Guo Junpeng Fan Rourou Xiao Dianxing Hu Wenju Peng Beibei Wang Chaoyang Sun |
| author_sort | Li Zhang |
| collection | DOAJ |
| description | Background Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.Methods We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.Results We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.Conclusions We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy. |
| first_indexed | 2024-04-09T17:18:28Z |
| format | Article |
| id | doaj.art-885194f4d4ed49448a58d817aacaae43 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-04-09T17:18:28Z |
| publishDate | 2023-04-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-885194f4d4ed49448a58d817aacaae432023-04-19T06:30:05ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-04-0111410.1136/jitc-2022-006070BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumorsLi Zhang0Xi Li1Gang Chen2Yu Fu3Bin Yang4Wenting Li5Jingbo Liu6Xu Qin7Gordon B Mills8Yaoyuan Cui9Xingyuan Hu10Funian Lu11Tianyu Qin12Zhe Hu13Ensong Guo14Junpeng Fan15Rourou Xiao16Dianxing Hu17Wenju Peng18Beibei Wang19Chaoyang Sun20Research Institute of General Surgery, Nanjing Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, ChinaGlobal Immunization Division, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia, USADepartment of Neurosurgery & Brain and Nerve Research Laboratory, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, ChinaApplied Research Collaboration North East and North Cumbria, NIHR, Gosforth, UKChina International Neuroscience Institute (China-INI), Beijing, ChinaDepartment of Obstetrics and Gynecology, The First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang, People`s Republic of China3 Dyson Vision Research Institute, Department of Ophthalmology, Weill Cornell Medical College, New York, USA1Department of Cardiology, The Huangpu Division of The First Affiliated Hospital, SUN Yat-sen University, Guangzhou 510700, China3 Division of Oncologic Sciences Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USADepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaNational Clinical Research Center for Gynecology and Obstetrics, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaDepartment of Gynecological Oncology, Tongji Hospital of Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei, People`s Republic of ChinaBackground Mismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.Methods We confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.Results We identified the positive correlation between BRD4 and MMR genes in transcriptional and translational aspects. Also, the inhibition of BRD4 transcriptionally reduced MMR genes expression, resulting in dMMR status and elevated mutation loads. Furthermore, prolonged exposure to AZD5153 promoted a persistent dMMR signature both in vitro and in vivo, enhancing tumor immunogenicity, and increased sensitivity to α-programmed death ligand-1 therapy despite the acquired drug resistance.Conclusions We demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.https://jitc.bmj.com/content/11/4/e006070.full |
| spellingShingle | Li Zhang Xi Li Gang Chen Yu Fu Bin Yang Wenting Li Jingbo Liu Xu Qin Gordon B Mills Yaoyuan Cui Xingyuan Hu Funian Lu Tianyu Qin Zhe Hu Ensong Guo Junpeng Fan Rourou Xiao Dianxing Hu Wenju Peng Beibei Wang Chaoyang Sun BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors Journal for ImmunoTherapy of Cancer |
| title | BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors |
| title_full | BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors |
| title_fullStr | BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors |
| title_full_unstemmed | BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors |
| title_short | BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors |
| title_sort | brd4 inhibition impairs dna mismatch repair induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in mmr proficient tumors |
| url | https://jitc.bmj.com/content/11/4/e006070.full |
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