Tissue-resident regulatory T cells exert dualistic anti-tumour and pro-repair function in the exocrine pancreas

Stockis, J.; Yip, T.; Raghunathan, S.; Garcia, C.; Lee, S.; Simpson, C.; Silvain, S.; Schuijs, M. J.; Araos, J.; Png, S.; Raddi, G.; Bricard, O.; So, T. Y.; Mack, S.; Papadopoulos, P.; Sawle, A.; Jodrell, D. I.; McKenzie, A. N. J.; Thaventhiran, J.; Clatworthy, M.; Biffi, G.; Saeb-Parsy, K.; Liston, A.; Halim, T. Y. F.

doi:10.1101/2024.02.15.580302

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bioRxiv · 10.1101/2024.02.15.580302

Tissue-resident regulatory T cells exert dualistic anti-tumour and pro-repair function in the exocrine pancreas

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Abstract

Regulatory T cells are fundamentally important for maintaining immune homeostasis, and their potent immune-suppressive roles make them attractive immunotherapeutic targets in cancer. Recent work suggests potential functions of tissue-resident Tregs (trTregs) in tissue-repair and epithelial cell homeostasis. Here, we describe a rare population of trTreg in the exocrine pancreas. We show that these cells share common features of trTregs, including expression of the IL-33 receptor ST2 and production of the epithelial growth factor Amphiregulin, and display an oligoclonal T cell receptor repertoire. Using a mouse model of acute pancreatitis, we show that pancreatic Tregs rapidly expand upon release of IL-33 by fibroblasts. Moreover, depletion of Tregs after initiation of pancreatic injury impairs the regeneration of the exocrine parenchyma. This effect is due, in part, through a direct effect of Tregs on acinar cell proliferation. Finally, we show that transient Treg depletion in established orthotopic pancreatic tumours leads to tumour rejection yet provokes long-lasting damages to surrounding exocrine parenchyma. In all, our results demonstrate the tissue-repair capacity of pancreatic Tregs, and highlight a dualistic role of these cells in the pancreatic tumour ecosystem, with their harmful immune-suppressive function in the tumour coupled to a beneficial tissue-repair function in the surrounding tissue.

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Stockis, J., Yip, T., Raghunathan, S., Garcia, C., Lee, S., Simpson, C., Silvain, S., Schuijs, M. J., Araos, J., Png, S., Raddi, G., Bricard, O., So, T. Y., Mack, S., Papadopoulos, P., Sawle, A., Jodrell, D. I., McKenzie, A. N. J., Thaventhiran, J., Clatworthy, M., Biffi, G., Saeb-Parsy, K., Liston, A., Halim, T. Y. F.. 2024-02-19. Tissue-resident regulatory T cells exert dualistic anti-tumour and pro-repair function in the exocrine pancreas. https://doi.org/10.1101/2024.02.15.580302

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