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: | 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 |
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| Authors: | Reshmi Nair, Tamsin R. M. Lannagan, Rene Jackstadt, Anna Andrusaite, John Cole, Caitlin Boyne, Robert J. B. Nibbs, Owen J. Sansom, Simon Milling |
| Source: | OncoImmunology, Vol 13, Iss 1 (2024) |
| Publisher Information: | Taylor & Francis Group, 2024. |
| Publication Year: | 2024 |
| Collection: | LCC:Immunologic diseases. Allergy LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
| Subject Terms: | immunotherapy, colorectal cancer, T-lymphocytes, myeloid cells, Check point inhibition, metabolism, Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282 |
| More Details: | 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. |
| Document Type: | article |
| File Description: | electronic resource |
| Language: | English |
| ISSN: | 2162402X 2162-402X |
| Relation: | https://doaj.org/toc/2162-402X |
| DOI: | 10.1080/2162402X.2024.2330194 |
| Access URL: | https://doaj.org/article/990e4b206f444c4f9e950f6acf44d5d0 |
| Accession Number: | edsdoj.990e4b206f444c4f9e950f6acf44d5d0 |
| Database: | Directory of Open Access Journals |
| ISSN: | 2162402X |
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| DOI: | 10.1080/2162402X.2024.2330194 |
| Published in: | OncoImmunology |
| Language: | English |