Checkpoint Inhibitor Colitis Shows Drug-Specific Differences in Immune Cell Reaction That Overlap With Inflammatory Bowel Disease and Predict Response to Colitis Therapy

Abstract

Objectives Checkpoint inhibitor (CPI)–associated colitis can limit therapy and has resemblance to inflammatory bowel disease (IBD). Studies exploring mechanistic similarities between these colitides are limited, yet therapeutic targets for either disorder could emerge from shared pathophysiology. Methods The morphology and inflammatory content of colonic biopsy specimens from anti–CTLA-4 and anti–PD-1/PD-L1 antibody-treated patients with CPI colitis were compared with initial biopsy specimens from patients with IBD. Predictors of the need for infliximab were sought in CPI patients. Results Biopsy specimens from CPI patients showed significantly lower chronicity scores and similar activity scores compared with patients with IBD. Anti–CTLA-4 and IBD groups showed equivalent CD8, CD4, PD-1, and PD-L1 expression, while FoxP3 scores were lower and CD68 scores were higher in anti–CTLA-4 compared with IBD biopsy specimens. Anti–PD-1/PD-L1 group had lower scores for CD8, CD4, and PD-1 and equivalent scores for FoxP3, PD-L1, and CD68 compared with IBD. Anti–CTLA-4 biopsy specimens had higher scores for CD8, PD-1, PD-L1, and CD68 than anti–PD-1/PD-L1 biopsy specimens. CD8/FoxP3 ratios and CD68 scores were higher among CPI patients requiring infliximab therapy for colitis compared with those responding to steroids. Conclusions The proinflammatory immune phenotype of anti–CTLA-4–associated colitis has significant overlap with IBD. CD8/FoxP3 ratios may predict therapeutic response in CPI-associated colitis.

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

“…In line with our findings, Coutzac et al described no significant differences in regulatory CD4 + T cell infiltrates between IBD and CIC; however, CD8 + T cell infiltrates were not compared [ 30 ]. In contrast to our findings, Lo et al described that IBD samples showed higher CD8 + T cell and CD4 + T cell counts and similar CD68 + cell counts when compared to PD-1 CIC samples, as well as similar CD8 + T cell and CD4 + T cell counts and lower CD68 + cell counts when compared with CTLA-4 CIC [ 31 ]. The limited number of IBD samples without distinction between UC and CD in the two abovementioned studies may account for the difference in findings.…”

Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

“… 103 104 Inflammatory bowel disease can present with CDI, even in the absence of immunosuppression, 105 suggesting that excessive inflammation can favour CDI. Given the similar pathophysiology in IBD and irAE colitis, 106 there may be a subset of patients that develop CDI because of the acquired hyperinflammatory state. Evolving evidence demonstrates that ICIs can alter the gut microbiota, and CDI may be a manifestation of this.…”

Immune Checkpoint Inhibitor-Associated Colitis: From Mechanism to Management

“…Additionally, colon ulceration, pancolitis, and high van der Heide or Mayo score are identified as the predictive factors correlated to the utilization for secondary immunosuppression (22,61,167). In addition, the biopsy specimens of CIC patients who required infliximab showed higher CD68 scores and CD8/FoxP3 ratios than those who responded to steroid (196).…”

“…Few prospective studies are conducted to illustrate the dose of IFX, while different guidelines showed almost universal recommendations that the initial dose is at 5 mg/kg (q2w) until symptoms improve (19,71,183,198). Seventy-two percent of patients recover with one IFX dose, though the requirement for two or three doses is common (19,77,196,197). However, IFX is reported to induce a rare type of hepatitis (199) and is limited in patients with hepatitis B virus or latent tuberculosis history (200,201).…”