Spatial transcriptomics and immunophenotyping uncover chronic inflammation-induced immune adaptations favoring dysplasia development in patients at risk of colitis-associated cancer

BACKGROUND AND AIMS: Colitis-associated cancer (CAC) is the most severe complication of inflammatory bowel disease (IBD). We hypothesized that chronic inflammation activates endogenous anti-inflammatory mechanisms that promote dysplasia by undermining immunosurveillance. Our aim was to determine chronic inflammation-induced immune cell reprogramming in IBD patients at risk for developing CAC. METHODS: This cohort study utilized GeoMx digital spatial profiling and imaging mass cytometry in 11 patients with either CAC or sporadic colorectal cancer (SCRC). Results from this discovery cohort were validated using immunohistochemistry/immunofluorescence in an independent cohort of CAC and SCRC patients (n = 10 and n = 14, respectively), as well as in an independent cohort of IBD patients with (n = 6) and without dysplasia (n = 18). RESULTS: Histologically uninflamed colon from patients who developed CAC displayed upregulated metabolism and stress response pathways as compared to SCRC patients, indicating ongoing epithelial stress-responses. Endogenous anti-inflammatory mechanisms included increased IL-10 expression by lamina propria IgA+ plasma cells and CD163+ macrophages. T cell recruitment and effector pathways were downregulated in CAC, which was associated with a decrease in CD8+ intraepithelial T cells (IELs) and reduced levels of granzyme B within CD8+ IELs. Decreased CD8+ IEL density was associated with CAC susceptibility, as IBD patients who developed dysplasia showed significantly lower levels of CD8+ IELs than IBD patients who never developed dysplasia. CONCLUSIONS: Chronic inflammation induces endogenous mechanisms to protect from inflammation-induced damage, including increased anti-inflammatory cytokine production and decreased levels of CD8+ IELs. While this may limit inflammation, these mechanisms may also reduce immunosurveillance, favoring the development of CAC.