Updates in the pathogenesis and management of immune-related enterocolitis, hepatitis and cardiovascular toxicities

Abstract

Immune checkpoint inhibitors (ICIs) have become a cornerstone of treatment for many solid organ malignancies. Alongside increasing use, the occurrence of immune-related adverse events (irAEs) has also increased and remains a significant challenge when treating patients with ICI. The underlying pathophysiology of irAE development for many organ systems is yet to be elucidated, but may involve unmasking of latent autoimmunity, increased T-cell recognition of shared antigens on cancer and normal tissue and ICI-triggered immune dysregulation with overactivation of proinflammatory pathways and suppression of immune control pathways. Management strategies for irAEs have historically been borrowed from paradigms for conventional autoimmune conditions such as inflammatory bowel disease and autoimmune hepatitis; however, recent translational efforts have clearly demonstrated key differences in underlying immune signalling pathways. As we begin to understand these differences, we must adapt a more targeted approach to immunosuppression and exercise a more nuanced approach with the multiple biologic agents available to mitigate ICI-related toxicity without reversing the antitumour effect of ICI. In this review, we focus on three key immune-related toxicities where recent clinical and translational work has provided nuanced insights into pathogenesis and treatment strategies: enterocolitis, hepatitis and cardiovascular toxicity including myocarditis.

Keywords: enterocolitis; hepatitis; immune-related adverse events; immunotherapy; myocarditis.

Figure 1

Pathways involved in the pathogenesis of ICI colitis. ICI leads to widespread T-cell activation. Increased CD8+ TRM cells and activated CTLs result in release of proinflammatory cytokines including IFN-γ and, via activation of macrophages, TNF-α. Increased CD4+ Th17 cells secrete IL-17, a potent chemokine promoting neutrophil migration. CD4+ Treg cells convert to a proinflammatory Th1 profile under the influence of IFN-γ, losing immune regulatory properties. Proinflammatory pathways recruit further peripheral immune cells into the inflammatory microenvironment resulting in intestinal inflammation, cell death and disruption to colon integrity. The influence of the gut microbiome, particularly enrichment with Bacteroides intestinalis, contributes to the proinflammatory environment. Created with BioRender.com. CTLA4, cytotoxic T-lymphocyte antigen-4; CTLs, cytotoxic T-cell lymphocytes; ICI, immune checkpoint inhibitor; IFN-γ, interferon-γ; IL, interleukin; JAK, Janus kinase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-β; Th17, T-helper 17; TNF-α, tumour necrosis factor-α; Treg, T-regulatory; TRM, tissue resident memory T cells.

Figure 2

Pathways involved in the pathogenesis of ICI hepatitis. ICIs are proposed to cause clonal expansion of CD8+ CTLs and to a lesser extent expansion of Th1 and Th17 CD4+ T cells which may directly cause cytotoxic cell damage. Clonal expansion of CD8+ CTLs is proposed to overcome immune tolerance and indirectly cause cell death via loss of tolerance and erroneous cytotoxic targeting of self-antigens. The innate immune system may be key in ICI hepatitis via ICI activation of monocytes and an increased number of MoMs resulting in a proinflammatory environment resulting in hepatocyte apoptosis. Finally, suppression of Treg cells leads to loss of anti-inflammatory negative feedback. Created with BioRender.com. CTLA, cytotoxic T-lymphocyte antigen; CTLs, cytotoxic T lymphocytes; ICI, immune checkpoint inhibitor; MoM, monocyte-derived macrophages; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; TGF-β, transforming growth factor-β; Th1, T-helper 1; Th17, T-helper 17; Treg, T-regulatory.

Figure 3

Pathways involved in the pathogenesis of ICI myocarditis. In a healthy state, immune checkpoints (CTLA4, PD-1) maintain immune tolerance by preventing autoreactive T-cell activation in the presence of self-antigens (e.g. α-myosin) and maintain T-cell anergy. ICIs block immune checkpoints (red crosses), which may result in activation of autoreactive CD8+ T cells that evade central tolerance, clonally proliferate in the peripheral blood and directly attack α-myosin antigens on cardiomyocytes resulting in myocyte inflammation and cell death. Migration and expansion of CCR2+ macrophages and resulting proinflammatory cytokine release further contribute to myocyte inflammation. Created with BioRender.com. APC, antigen presenting cell; CTLA4, cytotoxic T-lymphocyte antigen-4; ICI, immune checkpoint inhibitor; IFN-γ, interferon-γ; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1.