Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior

Suze A Jansen; Alessandro Cutilli; Coco de Koning; Marliek van Hoesel; Cynthia L Frederiks; Leire Saiz Sierra; Stefan Nierkens; Michal Mokry; Edward E S Nieuwenhuis; Alan M Hanash; Enric Mocholi; Paul J Coffer; Caroline A Lindemans

doi:10.1016/j.isci.2024.110072

Chemotherapy-induced intestinal epithelial damage directly promotes galectin-9-driven modulation of T cell behavior

iScience. 2024 May 22;27(6):110072. doi: 10.1016/j.isci.2024.110072. eCollection 2024 Jun 21.

Authors

Suze A Jansen^{1

2

3}, Alessandro Cutilli^{3

4}, Coco de Koning^{2

5}, Marliek van Hoesel^{1

3}, Cynthia L Frederiks^{3

4}, Leire Saiz Sierra^{1

3}, Stefan Nierkens^{2

5}, Michal Mokry^{1

6}, Edward E S Nieuwenhuis^{1

3

7}, Alan M Hanash⁸, Enric Mocholi^{3

4}, Paul J Coffer^{1

3

4}, Caroline A Lindemans^{1

2

3}

Affiliations

¹ Division of Pediatrics, University Medical Center Utrecht, Utrecht 3584GX, the Netherlands.
² Princess Máxima Center for Pediatric Oncology, Utrecht 3584CS, the Netherlands.
³ Regenerative Medicine Center, University Medical Center Utrecht, Utrecht 3584CT, the Netherlands.
⁴ Center of Molecular Medicine, University Medical Center Utrecht, Utrecht 3584CG, the Netherlands.
⁵ Center for Translational Immunology, University Medical Center Utrecht, 3584GX Utrecht, the Netherlands.
⁶ Department of Cardiology, University Medical Center Utrecht, Utrecht 3584GX, the Netherlands.
⁷ University College Roosevelt, Utrecht University, Middelburg 4331CB, the Netherlands.
⁸ Departments of Medicine and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.

Abstract

The intestine is vulnerable to chemotherapy-induced damage due to the high rate of intestinal epithelial cell (IEC) proliferation. We have developed a human intestinal organoid-based 3D model system to study the direct effect of chemotherapy-induced IEC damage on T cell behavior. Exposure of intestinal organoids to busulfan, fludarabine, and clofarabine induced damage-related responses affecting both the capacity to regenerate and transcriptional reprogramming. In ex vivo co-culture assays, prior intestinal organoid damage resulted in increased T cell activation, proliferation, and migration. We identified galectin-9 (Gal-9) as a key molecule released by damaged organoids. The use of anti-Gal-9 blocking antibodies or CRISPR/Cas9-mediated Gal-9 knock-out prevented intestinal organoid damage-induced T cell proliferation, interferon-gamma release, and migration. Increased levels of Gal-9 were found early after HSCT chemotherapeutic conditioning in the plasma of patients who later developed acute GVHD. Taken together, chemotherapy-induced intestinal damage can influence T cell behavior in a Gal-9-dependent manner which may provide novel strategies for therapeutic intervention.

Keywords: Cancer; Immunology; Molecular biology; Stem cells research.

Abstract

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