New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy
Abstract Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dict...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-07-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05999-3 |
| _version_ | 1797769335975968768 |
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| author | Taylor P. Uccello Maggie L. Lesch Sarah A. Kintzel Lauren B. Gradzewicz Lillia Lamrous Shawn P. Murphy Fergal J. Fleming Bradley N. Mills Joseph D. Murphy Angela Hughson Gary Hannon Jesse Garrett-Larsen Haoming Qiu Michael G. Drage Jian Ye Nicholas W. Gavras David C. Keeley Tanzy M. T. Love Elizabeth A. Repasky Edith M. Lord David C. Linehan Scott A. Gerber |
| author_facet | Taylor P. Uccello Maggie L. Lesch Sarah A. Kintzel Lauren B. Gradzewicz Lillia Lamrous Shawn P. Murphy Fergal J. Fleming Bradley N. Mills Joseph D. Murphy Angela Hughson Gary Hannon Jesse Garrett-Larsen Haoming Qiu Michael G. Drage Jian Ye Nicholas W. Gavras David C. Keeley Tanzy M. T. Love Elizabeth A. Repasky Edith M. Lord David C. Linehan Scott A. Gerber |
| author_sort | Taylor P. Uccello |
| collection | DOAJ |
| description | Abstract Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I Interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC. |
| first_indexed | 2024-03-12T21:07:31Z |
| format | Article |
| id | doaj.art-e9b3abc8040b4f838d19d476c4b23ebc |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T21:07:31Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-e9b3abc8040b4f838d19d476c4b23ebc2023-07-30T11:25:45ZengNature Publishing GroupCell Death and Disease2041-48892023-07-0114711210.1038/s41419-023-05999-3New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapyTaylor P. Uccello0Maggie L. Lesch1Sarah A. Kintzel2Lauren B. Gradzewicz3Lillia Lamrous4Shawn P. Murphy5Fergal J. Fleming6Bradley N. Mills7Joseph D. Murphy8Angela Hughson9Gary Hannon10Jesse Garrett-Larsen11Haoming Qiu12Michael G. Drage13Jian Ye14Nicholas W. Gavras15David C. Keeley16Tanzy M. T. Love17Elizabeth A. Repasky18Edith M. Lord19David C. Linehan20Scott A. Gerber21Department of Microbiology and Immunology, University of Rochester Medical CenterDepartment of Microbiology and Immunology, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Obstetrics and Gynecology, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Microbiology and Immunology, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Radiation Oncology, University of Rochester Medical CenterDepartment of Pathology and Laboratory Medicine, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Biostatistics and Computational Biology, University of Rochester Medical CenterRoswell Park Comprehensive Cancer Institute, University at BuffaloDepartment of Microbiology and Immunology, University of Rochester Medical CenterDepartment of Surgery, University of Rochester Medical CenterDepartment of Microbiology and Immunology, University of Rochester Medical CenterAbstract Rectal cancer ranks as the second leading cause of cancer-related deaths. Neoadjuvant therapy for rectal cancer patients often results in individuals that respond well to therapy and those that respond poorly, requiring life-altering excision surgery. It is inadequately understood what dictates this responder/nonresponder divide. Our major aim is to identify what factors in the tumor microenvironment drive a fraction of rectal cancer patients to respond to radiotherapy. We also sought to distinguish potential biomarkers that would indicate a positive response to therapy and design combinatorial therapeutics to enhance radiotherapy efficacy. To address this, we developed an orthotopic murine model of rectal cancer treated with short course radiotherapy that recapitulates the bimodal response observed in the clinic. We utilized a robust combination of transcriptomics and protein analysis to identify differences between responding and nonresponding tumors. Our mouse model recapitulates human disease in which a fraction of tumors respond to radiotherapy (responders) while the majority are nonresponsive. We determined that responding tumors had increased damage-induced cell death, and a unique immune-activation signature associated with tumor-associated macrophages, cancer-associated fibroblasts, and CD8+ T cells. This signature was dependent on radiation-induced increases of Type I Interferons (IFNs). We investigated a therapeutic approach targeting the cGAS/STING pathway and demonstrated improved response rate following radiotherapy. These results suggest that modulating the Type I IFN pathway has the potential to improve radiation therapy efficacy in RC.https://doi.org/10.1038/s41419-023-05999-3 |
| spellingShingle | Taylor P. Uccello Maggie L. Lesch Sarah A. Kintzel Lauren B. Gradzewicz Lillia Lamrous Shawn P. Murphy Fergal J. Fleming Bradley N. Mills Joseph D. Murphy Angela Hughson Gary Hannon Jesse Garrett-Larsen Haoming Qiu Michael G. Drage Jian Ye Nicholas W. Gavras David C. Keeley Tanzy M. T. Love Elizabeth A. Repasky Edith M. Lord David C. Linehan Scott A. Gerber New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy Cell Death and Disease |
| title | New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy |
| title_full | New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy |
| title_fullStr | New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy |
| title_full_unstemmed | New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy |
| title_short | New insights into the responder/nonresponder divide in rectal cancer: Damage-induced Type I IFNs dictate treatment efficacy and can be targeted to enhance radiotherapy |
| title_sort | new insights into the responder nonresponder divide in rectal cancer damage induced type i ifns dictate treatment efficacy and can be targeted to enhance radiotherapy |
| url | https://doi.org/10.1038/s41419-023-05999-3 |
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