Chemotherapy-induced intestinal injury promotes Galectin-9-driven modulation of T cell function

Coffer, P. J.; Lindemans, C. A.; Cutilli, A.; Jansen, S. A.; de Koning, C. C.; van Hoesel, M.; Nierkens, S.; Mokry, M.; Nieuwenhuis, E. E.; Mocholi, E.; Hanash, A.

doi:10.1101/2023.04.30.538862

bioRxiv · 10.1101/2023.04.30.538862

Chemotherapy-induced intestinal injury promotes Galectin-9-driven modulation of T cell function

Coffer, P. J.·Lindemans, C. A.·Cutilli, A.·Jansen, S. A.·de Koning, C. C.·van Hoesel, M.·Nierkens, S.·Mokry, M.·Nieuwenhuis, E. E.·Mocholi, E.·Hanash, A.

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Abstract

The intestine is vulnerable to chemotherapy-induced toxicity due to its high epithelial proliferative rate, making gut toxicity an off-target effect in several cancer treatments, including conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT). In allo-HCT, intestinal damage is an important factor in the development of Graft-versus-Host Disease (GVHD), an immune complication in which donor immune cells attack the recipients tissues. Here, we developed a novel human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced intestinal epithelial damage on T cell behavior. Chemotherapy treatment using busulfan, fludarabine, and clofarabine led to damage responses in organoids resulting in increased T cell migration, activation, and proliferation in ex-vivo co-culture assays. We identified galectin-9 (Gal-9), a beta-galactoside-binding lectin released by damaged organoids, as a key molecule mediating T cell responses to damage. Increased levels of Gal-9 were also found in the plasma of allo-HCT patients who later developed acute GVHD, supporting the predictive value of the model system in the clinical setting. This study highlights the potential contribution of chemotherapy-induced epithelial damage to the pathogenesis of intestinal GVHD through direct effects on T cell activation and trafficking promoted by galectin-9.

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Coffer, P. J., Lindemans, C. A., Cutilli, A., Jansen, S. A., de Koning, C. C., van Hoesel, M., Nierkens, S., Mokry, M., Nieuwenhuis, E. E., Mocholi, E., Hanash, A.. 2023-04-30. Chemotherapy-induced intestinal injury promotes Galectin-9-driven modulation of T cell function. https://doi.org/10.1101/2023.04.30.538862

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