Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8 + T cells and an infiltration pattern that resembles ulcerative colitis

Abstract

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease.

Dasatinib-induced Crohn’s-like colitis

“…This peculiar histological pattern can lead to a misdiagnosis of Crohn’s colitis if information of Dasatinib use is not provided to the pathologist, as seen in our case 1. Various other therapeutic agents (ie, immune checkpoint inhibitors) can induce colitis with IBD-like features; more frequently showing an ulcerative colitis-like pattern13 14 but cases with CD-like features have also been reported with anti-Tumour Necrosis Factor (TNF)-alpha therapy and rituximab 14…”

Gut inflammation induced by drugs: Can pathology help to differentiate from inflammatory bowel disease?

“…Histological clues to ICI colitis include: crypt epithelial cell apoptosis 25 , 27 , 28 (variable definitions, including more than 3 apoptotic bodies within epithelium of 10 crypts, 23 more than one apoptotic cell per biopsy, 29 more than 5 apoptotic bodies per 100 crypts 9 ). Excess apoptosis can be seen without accompanying inflammation, producing a GVHD‐like pattern of injury, or in combination with acute colitis or chronic active colitis 17 (Figure 2a ) atrophic crypts with attenuation of crypt epithelium, 17 , 18 , 30 sometimes with an intraluminal admixture of apoptotic debris and inflammatory cells 13 , 17 , 18 , 23 intra‐epithelial lymphocytosis (more than 10 intraepithelial lymphocytes within 100 surface epithelial cells) 23 , 25 , 27 , 30 , 31 a mild (rather than moderate/severe) degree of CAD 16 , 28 (Figure 2a – c ), less frequent basal plasmacytosis, 28 fewer lamina propria plasma cells, less subcryptal inflammation, lower overall chronicity scores compared to IBD 23 Lesser degree of cryptitis and crypt abscesses compared to UC 28 …”

“…atrophic crypts with attenuation of crypt epithelium, 17 , 18 , 30 sometimes with an intraluminal admixture of apoptotic debris and inflammatory cells 13 , 17 , 18 , 23 …”

“…intra‐epithelial lymphocytosis (more than 10 intraepithelial lymphocytes within 100 surface epithelial cells) 23 , 25 , 27 , 30 , 31 …”

“…Several studies 23 , 28 , 30 , 31 have compared lymphocytic subsets between ICI colitis and IBD with variable results. For example, one study reported similar CD8 + T‐lymphocyte counts and immune cell infiltration patterns between UC and ICI colitis, 30 and another described higher CD8 + and CD4 + T‐lymphocytes in IBD compared to anti‐PD‐1 colitis. 23 Analysis of lymphocytic subsets and immune cell infiltration patterns is not currently used in practice for diagnostic purposes.…”