Checkpoint inhibitor-induced colitis shares mucosal histopathological features with inflammatory bowel and graft-versus-host disease

Background: Checkpoint inhibitor-induced colitis (CIC) is a severe side-effect of immune-checkpoint inhibitors (ICI). Its pathophysiology is poorly understood, impairing improvement of prevention and treatment strategies. CD4+ and CD8+ T cells and CD68+ macrophages are thought to be critical in colitis development. Studies suggest that CIC is histopathologically similar to inflammatory bowel disease (IBD) and acute graft-versus-host disease (aGVHD) colitis. However, the histopathology of these entities has not been directly compared. We aimed to improve knowledge on CIC by performing a direct immunohistochemical comparison of CIC, IBD and aGVHD. Methods: Archival formalin fixed paraffin-embedded colon biopsies obtained during routine diagnostic procedures from consecutive, eligible, treatment-naïve patients with CIC, IBD and aGVHD (all n=20) were studied. Biopsies from patients without histopathological abnormalities served as controls (n=20). Immunohistochemical staining was performed for CD4+ and CD8+ T cells and CD68+ macrophages. In each biopsy 3 mucosal areas with highest immune cell density were selected for cell counting. The number of cells/hotspot were classified as 0-10, 10-50, 50-100, 100-150 and >150. Next, the distribution of these cells was studied and compared between patient groups. We used descriptive statistics to depict and compare cell counts and infiltration patterns among patient groups. Results: In CIC higher CD4+ and CD8+ T cell density (100-150 cells/hotspot in most patients) was observed compared to IBD, aGVHD and controls (50-100 cells/hotspot in most patients in each group). In contrast to controls, some IBD (12%) and aGVHD (15%) patients had a CD4+ T cell count of 100-150 cells/hotspot and some IBD (20%) and aGVHD (21%) patients had a CD8+ T cell count of 100-150 cells/hotspot. CIC, IBD aGVHD and controls shared a similar CD68+ macrophage count (50-100 cells/hotspot in most patients in each group). During cell counting we noted that cells infiltrated the superficial (subepithelium) and deep (lamina propria and muscularis mucosae) layers of the mucosa with either a scattered or patchy distribution. We recognized 4 distribution patterns: A) superficial diffuse, deep scattered/patchy; B) superficial scattered/patchy, deep diffuse; C) superficial and deep diffuse; D) superficial and deep scattered/patchy. The most prevalent infiltration pattern of CD4+ T cells was D in CIC patients (74%), C in IBD patients (47%), B in aGVHD patients (54%) and A in control patients (83%). The most prevalent infiltration pattern of CD8+ T cells was D in CIC (45%), and A in IBD (85%), aGVHD (63%) and all control patients. In most patients, CD68+ macrophages occurred in pattern A (56% of CIC, 58% of IBD, 59% of aGVHD, 100% of controls). Conclusion: CIC has a distinct immunohistopathological pattern that shares key elements with both IBD and aGVHD