Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity
Summary: Patients with colorectal cancers (CRCs) that have microsatellite instability (MSI) (MSI CRCs) face a better prognosis than those with the more common chromosomal instability (CIN) subtype (CIN CRCs) due to improved T cell-mediated anti-tumor immune responses. Previous investigations identif...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-02-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724015286 |
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| author | Shayla R. Mosley Angie Chen David N.W. Doell Siwon Choi Courtney Mowat Felix Meier-Stephenson Vanessa Meier-Stephenson Kristi Baker |
| author_facet | Shayla R. Mosley Angie Chen David N.W. Doell Siwon Choi Courtney Mowat Felix Meier-Stephenson Vanessa Meier-Stephenson Kristi Baker |
| author_sort | Shayla R. Mosley |
| collection | DOAJ |
| description | Summary: Patients with colorectal cancers (CRCs) that have microsatellite instability (MSI) (MSI CRCs) face a better prognosis than those with the more common chromosomal instability (CIN) subtype (CIN CRCs) due to improved T cell-mediated anti-tumor immune responses. Previous investigations identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find that cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and improves cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates that MSI cyDNA is enriched in microsatellites, which, upon DC uptake, induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. DNA-damaging therapies also modulate cyDNA stimulation capacity, with radiation inducing larger cyDNA sizes and increased mitochondrial DNA content. Identifying highly stimulatory endogenous cyDNAs such as those in MSI CRCs will allow for optimized development of DNA-based STING agonist therapies to improve the responses of CIN CRCs with CIN to immunotherapies. |
| format | Article |
| id | doaj-art-4228430ec48846daa702ffa93cfdb763 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-4228430ec48846daa702ffa93cfdb7632025-01-26T05:03:48ZengElsevierCell Reports2211-12472025-02-01442115177Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunityShayla R. Mosley0Angie Chen1David N.W. Doell2Siwon Choi3Courtney Mowat4Felix Meier-Stephenson5Vanessa Meier-Stephenson6Kristi Baker7Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; Corresponding authorDepartment of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, CanadaDepartment of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, CanadaDepartment of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, CanadaDepartment of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, AB T6G 1Z2, Canada; Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, AB T6G 2R3, Canada; Corresponding authorSummary: Patients with colorectal cancers (CRCs) that have microsatellite instability (MSI) (MSI CRCs) face a better prognosis than those with the more common chromosomal instability (CIN) subtype (CIN CRCs) due to improved T cell-mediated anti-tumor immune responses. Previous investigations identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find that cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and improves cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates that MSI cyDNA is enriched in microsatellites, which, upon DC uptake, induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. DNA-damaging therapies also modulate cyDNA stimulation capacity, with radiation inducing larger cyDNA sizes and increased mitochondrial DNA content. Identifying highly stimulatory endogenous cyDNAs such as those in MSI CRCs will allow for optimized development of DNA-based STING agonist therapies to improve the responses of CIN CRCs with CIN to immunotherapies.http://www.sciencedirect.com/science/article/pii/S2211124724015286CP: CancerCP: Immunology |
| spellingShingle | Shayla R. Mosley Angie Chen David N.W. Doell Siwon Choi Courtney Mowat Felix Meier-Stephenson Vanessa Meier-Stephenson Kristi Baker Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity Cell Reports CP: Cancer CP: Immunology |
| title | Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity |
| title_full | Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity |
| title_fullStr | Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity |
| title_full_unstemmed | Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity |
| title_short | Cytosolic DNA composition is determined by genomic instability mechanism and regulates dendritic cell-mediated anti-tumor immunity |
| title_sort | cytosolic dna composition is determined by genomic instability mechanism and regulates dendritic cell mediated anti tumor immunity |
| topic | CP: Cancer CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724015286 |
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