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

Nair, R., Lannagan, T. R.M., Jackstadt, R., Andrusaite, A., Cole, J., Boyne, C., Nibbs, R. J.B. , Sansom, O. J. and Milling, S. (2024) 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, 13(1), 2330194. (doi: 10.1080/2162402X.2024.2330194)

Abstract

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.

• Item Type: Articles
• Additional Information: This research work was funded by the college of MVLS, University of Glasgow, UK. Sansom group is funded by Cancer Research UK [A31287 and A21139].
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Nibbs, Professor Rob and Boyne, Miss Caitlin and Andrusaite, Ms Anna and Cole, Mr John and Milling, Professor Simon and NAIR, RESHMI and Sansom, Professor Owen
• Authors: Nair, R., Lannagan, T. R.M., Jackstadt, R., Andrusaite, A., Cole, J., Boyne, C., Nibbs, R. J.B., Sansom, O. J., and Milling, S.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: OncoImmunology
• Publisher: Taylor & Francis
• ISSN: 2162-4011
• ISSN (Online): 2162-402X
• Copyright Holders: Copyright: © 2024 The Author(s)
• First Published: First published in OncoImmunology 13(1): 2330194
• Publisher Policy: Reproduced under a Creative Commons licence