Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Reschke, Robin; Shapiro, Jason W.; Yu, Jovian; Rouhani, Sherin J.; Olson, Daniel J.; Zha, Yuanyuan; Gajewski, Thomas F.

doi:10.1158/2326-6066.cir-22-0362

Cited by 40 publications

(47 citation statements)

References 35 publications

(31 reference statements)

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“…As ICI-colitis appears dominantly Th1/Tc1-mediated disease, 14,15,17,43 Jak inhibition could be another treatment strategy in ICI-colitis. 44 Its safety from a tumor response perspective is presently not well established, however.…”

Section: Discussionmentioning

confidence: 99%

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

Eijs

Linde

Baars

et al. 2023

Preprint

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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 CD8+T cells are significantly more abundant (and 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 (TRM) 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+TRMcells as potentially targetable drivers of ICI-colitis.

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Section: Discussionmentioning

confidence: 99%

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

Eijs

Linde

Baars

et al. 2023

Preprint

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“…In our recent publication we reported that T RM cells dominated in the inflammatory reactions associated with irAE-dermatitis and -colitis following checkpoint blockade immunotherapy. Biopsies showed and expansion of CD4+ and CD8+ T RM cells in percentage and numbers as assessed by multi-spectral immune fluorescence staining 5 . Spatial transcriptomics and confirmatory RNAscope were utilized to examine the transcriptional signatures of these expanded T RM cells.…”

Section: T Rm Cells and Immune Related Adverse Eventsmentioning

confidence: 99%

Tissue-resident memory T cells in immune-related adverse events: friend or foe?

Reschke

Gajewski

2023

OncoImmunology

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Many cancer patients experience toxicity during checkpoint blockade immunotherapy, which often leads to treatment discontinuation. To this end, understanding the mechanisms mediating immune-related adverse events (irAE) should ultimately enable improvement in clinical outcomes. Recent work has revealed that tissue-resident memory T (T RM ) cells are locally expanded in irAE-dermatitis and -colitis.

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“…29 Spatial transcriptomic data have shown a higher expression of inhibitory receptors in dermatitis cases, as well as a portion of tissue-resident memory T cells aggregated to the inflamed part of the skin. 29…”

Section: Skin Cancermentioning

confidence: 99%

Spatial transcriptomics in human skin research

Tekkela

Theocharidis

McGrath

et al. 2023

Experimental Dermatology

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Tissues and organs of multicellular organisms are spatially organised by the compartmentalisation of cell types and subpopulations that are coordinated in internal gene regulatory networks, and by signalling from their surrounding tissue environment. In order to perform a subset of biologic processes, these cells differ in terms of localisation, morphology and gene expression patterns. 1 The development of single-cell methods has enabled studies that can retain cellular properties and heterogeneity at a single-cell resolution, which has led to a more detailed understanding of physiologic and disease conditions. 2 One of the most popular methods, single-cell RNA-sequencing (scRNA-seq), has made it possible to profile the whole transcriptome of each individual cell. 3,4 However, it results in the loss of information on spatial relationships among the cell populations since it entails dismantling of the original tissue into single-cell suspensions through mechanical and enzymatic dissociation steps, which could perturb or alter the cell's gene expression. 5 Recently, various techniques have been developed aiming for transcriptome mapping while preserving the spatial location of the expressed transcripts within intact tissues. 6 These methods, collectively known as spatial transcriptomics (ST), have been voted as the method of the year 2020 by Nature Methods and expect to provide remarkable novel insights in the

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Checkpoint Blockade–Induced Dermatitis and Colitis Are Dominated by Tissue-Resident Memory T Cells and Th1/Tc1 Cytokines

Cited by 40 publications

References 35 publications

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

Highly multiplexed spatial analysis identifies tissue-resident memory T cells as drivers of ulcerative and immune checkpoint inhibitor induced colitis

Tissue-resident memory T cells in immune-related adverse events: friend or foe?

Spatial transcriptomics in human skin research

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