Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor colitis
Mick J.M. van Eijs,
José J.M. ter Linde,
Matthijs J.D. Baars,
Mojtaba Amini,
Miangela M. Laclé,
Eelco C. Brand,
Eveline M. Delemarre,
Julia Drylewicz,
Stefan Nierkens,
Rik J. Verheijden,
Bas Oldenburg,
Yvonne Vercoulen,
Karijn P.M. Suijkerbuijk,
Femke van Wijk
Affiliations
Mick J.M. van Eijs
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Department of Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
José J.M. ter Linde
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Matthijs J.D. Baars
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
Mojtaba Amini
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; UCyTOF.nl, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Miangela M. Laclé
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Eelco C. Brand
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Eveline M. Delemarre
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands
Julia Drylewicz
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands
Stefan Nierkens
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Princess Máxima Center for Pediatric Oncology, P.O. Box 113, 3720 AC Utrecht, the Netherlands
Rik J. Verheijden
Department of Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Bas Oldenburg
Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Yvonne Vercoulen
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; UCyTOF.nl, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
Karijn P.M. Suijkerbuijk
Department of Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
Femke van Wijk
Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Lundlaan 6, 3584 EA Utrecht, the Netherlands; Corresponding author
Summary: Colitis is a prevalent adverse event associated with immune checkpoint inhibitor (ICI) therapy with similarities to inflammatory bowel disease. Incomplete mechanistic understanding of ICI colitis curtails evidence-based treatment. Given the often-overlooked connection between tissue architecture and mucosal immune cell function, we here applied imaging mass cytometry (IMC) to gain spatial proteomic insight in ICI colitis in comparison to ulcerative colitis (UC). Using a cell segmentation pipeline that simultaneously utilizes high-resolution nuclear imaging and high-multiplexity IMC, we show that intra-epithelial CD8+ T cells are significantly more abundant (and numerically dominant) in anti-PD-1 ± anti-CTLA-4-induced colitis compared to anti-CTLA-4-induced colitis and UC. We identified activated, cycling CD8+ tissue-resident memory T(RM) cells at the lamina propria-epithelial interface as drivers of cytotoxicity in ICI colitis and UC. Moreover, we found that combined ICI-induced colitis featured highest granzyme B levels both in tissue and serum. Together, these data reinforce CD8+ TRM cells as potentially targetable drivers of ICI colitis.
