Multiplex spatial omics reveals changes in immune-epithelial crosstalk during inflammation and dysplasia development in chronic IBD patients
Matthijs J.D. Baars,
Evelien Floor,
Neeraj Sinha,
José J.M. ter Linde,
Stephanie van Dam,
Mojtaba Amini,
Isaäc J. Nijman,
Joren R. ten Hove,
Julia Drylewicz,
G.Johan A. Offerhaus,
Miangela M. Laclé,
Bas Oldenburg,
Yvonne Vercoulen
Affiliations
Matthijs J.D. Baars
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
Evelien Floor
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Neeraj Sinha
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
José J.M. ter Linde
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Stephanie van Dam
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; Oncode Institute, Utrecht, the Netherlands
Mojtaba Amini
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; UCyTOF, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
Isaäc J. Nijman
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; USEQ, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands
Joren R. ten Hove
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Julia Drylewicz
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, EA, Utrecht 3584, the Netherlands
G.Johan A. Offerhaus
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Miangela M. Laclé
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Bas Oldenburg
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, CX, Utrecht 3584, the Netherlands
Yvonne Vercoulen
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; UCyTOF, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, CX, Utrecht 3584, the Netherlands; Corresponding author
Summary: Patients with long-standing inflammatory bowel disease (IBD) face an increased risk of developing colitis-associated cancer (CAC). Although IBD-induced prolonged inflammation seems to be involved in CAC pathogenesis, the specific molecular changes that contribute remain unknown. Here, we applied digital spatial RNA profiling, RNAscope, and imaging mass cytometry to examine paired uninflamed, inflamed, and early dysplastic mucosa of patients with IBD. We observed robust type 3 (IL-17) responses during inflammation, accompanied by elevated JAK-STAT signaling and phosphorylated STAT3 (P-STAT3) levels, with both inflamed and dysplastic mucosa displaying immune cell activation. Higher stromal P-STAT3 was detected in uninflamed and inflamed mucosa of patients who eventually developed dysplasia. CD8a+ T cells did not infiltrate inflamed or dysplastic epithelial regions in these patients, while control patients showed elevated CD8a in inflamed mucosa. Our study reveals distinct inflammatory patterns throughout CAC development, marked by an activated IL-17 pathway, engaged STAT3, and diminished cytotoxic T cell infiltration.
