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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
- Source :
- OncoImmunology, Vol 13, Iss 1 (2024)
- Publication Year :
- 2024
- Publisher :
- Taylor & Francis Group, 2024.
-
Abstract
- ABSTRACTColorectal 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.
Details
- Language :
- English
- ISSN :
- 2162402X
- Volume :
- 13
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- OncoImmunology
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.990e4b206f444c4f9e950f6acf44d5d0
- Document Type :
- article
- Full Text :
- https://doi.org/10.1080/2162402X.2024.2330194