Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance
Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20–30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) diff...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2330194 |
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| author | Reshmi Nair Tamsin R. M. Lannagan Rene Jackstadt Anna Andrusaite John Cole Caitlin Boyne Robert J. B. Nibbs Owen J. Sansom Simon Milling |
| author_facet | Reshmi Nair Tamsin R. M. Lannagan Rene Jackstadt Anna Andrusaite John Cole Caitlin Boyne Robert J. B. Nibbs Owen J. Sansom Simon Milling |
| author_sort | Reshmi Nair |
| collection | DOAJ |
| description | Colorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20–30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), “KPN”, which resembles the human ‘CMS4’-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC. |
| format | Article |
| id | doaj-art-990e4b206f444c4f9e950f6acf44d5d0 |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-990e4b206f444c4f9e950f6acf44d5d02024-12-03T13:49:35ZengTaylor & Francis GroupOncoImmunology2162-402X2024-12-0113110.1080/2162402X.2024.2330194Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistanceReshmi Nair0Tamsin R. M. Lannagan1Rene Jackstadt2Anna Andrusaite3John Cole4Caitlin Boyne5Robert J. B. Nibbs6Owen J. Sansom7Simon Milling8School of infection and immunity, University of Glasgow, Glasgow, UKCancer Research UK Scotland Institute, Glasgow, UKCancer Research UK Scotland Institute, Glasgow, UKSchool of infection and immunity, University of Glasgow, Glasgow, UKSchool of infection and immunity, University of Glasgow, Glasgow, UKSchool of infection and immunity, University of Glasgow, Glasgow, UKSchool of infection and immunity, University of Glasgow, Glasgow, UKCancer Research UK Scotland Institute, Glasgow, UKSchool of infection and immunity, University of Glasgow, Glasgow, UKColorectal cancer (CRC) is the third most prevalent cancer worldwide with a high mortality rate (20–30%), especially due to metastasis to adjacent organs. Clinical responses to chemotherapy, radiation, targeted and immunotherapies are limited to a subset of patients making metastatic CRC (mCRC) difficult to treat. To understand the therapeutic modulation of immune response in mCRC, we have used a genetically engineered mouse model (GEMM), “KPN”, which resembles the human ‘CMS4’-like subtype. We show here that transforming growth factor (TGF-β1), secreted by KPN organoids, increases cancer cell proliferation, and inhibits splenocyte activation in vitro. TGF-β1 also inhibits activation of naive but not pre-activated T cells, suggesting differential effects on specific immune cells. In vivo, the inhibition of TGF-β inflames the KPN tumors, causing infiltration of T cells, monocytes and monocytic intermediates, while reducing neutrophils and epithelial cells. Co-inhibition of TGF-β and PD-L1 signaling further enhances cytotoxic CD8+T cells and upregulates innate immune response and interferon gene signatures. However, simultaneous upregulation of cancer-related metabolic genes correlated with limited control of tumor burden and/or progression despite combination treatment. Our study illustrates the importance of using GEMMs to predict better immunotherapies for mCRC.https://www.tandfonline.com/doi/10.1080/2162402X.2024.2330194immunotherapycolorectal cancerT-lymphocytesmyeloid cellsCheck point inhibitionmetabolism |
| spellingShingle | Reshmi Nair Tamsin R. M. Lannagan Rene Jackstadt Anna Andrusaite John Cole Caitlin Boyne Robert J. B. Nibbs Owen J. Sansom Simon Milling Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance OncoImmunology immunotherapy colorectal cancer T-lymphocytes myeloid cells Check point inhibition metabolism |
| title | Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance |
| title_full | Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance |
| title_fullStr | Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance |
| title_full_unstemmed | Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance |
| title_short | Co-inhibition of TGF-β and PD-L1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses, innate cells and T cells, alongside metabolic changes and tumor resistance |
| title_sort | co inhibition of tgf β and pd l1 pathways in a metastatic colorectal cancer mouse model triggers interferon responses innate cells and t cells alongside metabolic changes and tumor resistance |
| topic | immunotherapy colorectal cancer T-lymphocytes myeloid cells Check point inhibition metabolism |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2330194 |
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