Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration

Abstract

Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)–mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4–mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.

Microbiome influencers of checkpoint blockade–associated toxicity

“…These reveal inflammatory lesions in the ileum and/or colon marked by granulocytic infiltration, epithelial apoptosis, cryptitis, disruption of crypt architecture, and other characteristic signs of intestinal inflammation ( Tian et al, 2018 ). Immune profiling of ICI colitis biopsies identified infiltration and activation of cytotoxic T lymphocytes, tissue-resident T cells, and neutrophils, along with increased myeloid cytokines and neutrophil chemoattractants ( Hailemichael et al, 2022 ; Luoma et al, 2020 ; Zhou et al, 2023 ). Treatment of ICI colitis depends on the severity, with corticosteroids often used in grade 2 or higher, with or without non-steroid immunomodulators such as blockade of TNF-α (Infliximab) or the gut-homing α4β7 integrin (Vedolizumab; Schneider et al, 2021 ; Tian et al, 2018 ).…”

“…Inflammatory cytokines including IL-1β, TNF-α, and IL-6 are linked with effects of the fecal microbiome on ICI colitis; IL-6 also drives irAEs in other organs ( Andrews et al, 2021 ; Dimitriou et al, 2021 ; Hailemichael et al, 2022 ; Kim et al, 2017 ; Perez-Ruiz et al, 2019 ; Uemura et al, 2016 ; Zhou et al, 2023 ). While IL-1β blockade reduced ICI colitis severity in mice, IL-6 inhibition improved tumor response to ICI and suppressed irAE symptoms in preclinical models, and is being pursued as an approach to alleviate irAEs in patients ( Andrews et al, 2021 ; Dimitriou et al, 2021 ; Hailemichael et al, 2022 ; Kim et al, 2017 ; Uemura et al, 2016 ; Zhou et al, 2023 ). These inflammatory cytokines are induced by MAMPs, often in myeloid and DC populations, suggesting microbiome-associated factors affect their production by innate immune subsets.…”

“…IFN-γ and IL-17, which are generally produced by lymphocytes, are linked with ICI colitis and skin irAEs ( Hailemichael et al, 2022 ; Hu et al, 2022 ; Zhou et al, 2023 ). IFN-γ is favorable in the context of ICI and tumor immune responses, yet IFN-γ can promote off-target inflammation.…”

“…Moreover, IL-17 is an inflammatory factor involved in production of myeloid cells that induce tissue damage ( Kanai et al, 2012 ; Xu and Cao, 2010 ). As IL-6 drives Th17 generation and is one of the most elevated cytokines in human ICI colitis, results to date suggest an IL-6–Th17 axis contributes to irAEs ( Hailemichael et al, 2022 ; Zhou et al, 2023 ).…”

“…Autoimmune and autoinflammatory responses have been implicated as irAE-driving mechanisms ( Kuchroo et al, 2021 ; Morad et al, 2022 ; Sullivan and Weber, 2022 ). Moreover, evidence indicates microbiome effects on irAEs, particularly at barrier sites such as the GI tract and skin ( Hu et al, 2022 ; McCulloch et al, 2022 ; Morad et al, 2022 ; Park et al, 2022 ; Zhou et al, 2023 ). Here, we discuss the microbiome influence on ICI efficacy and dive more deeply into developing links with irAEs, with the goal of spurring new research and clinical strategies to improve ICI outcomes.…”