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Review
. 2021 Oct 29:12:768957.
doi: 10.3389/fimmu.2021.768957. eCollection 2021.

Mechanisms of Immune Checkpoint Inhibitor-Mediated Colitis

Harm Westdorp  1   2 , Mark W D Sweep  1   2 , Mark A J Gorris  1   3 , Frank Hoentjen  4   5 , Marye J Boers-Sonderen  2 , Rachel S van der Post  6 , Michel M van den Heuvel  7 , Berber Piet  1   7 , Annemarie Boleij  6 , Haiko J Bloemendal  2 , I Jolanda M de Vries  1
Affiliations
Review

Mechanisms of Immune Checkpoint Inhibitor-Mediated Colitis

Harm Westdorp et al. Front Immunol. .

Abstract

Immune checkpoint inhibitors (ICIs) have provided tremendous clinical benefit in several cancer types. However, systemic activation of the immune system also leads to several immune-related adverse events. Of these, ICI-mediated colitis (IMC) occurs frequently and is the one with the highest absolute fatality. To improve current treatment strategies, it is important to understand the cellular mechanisms that induce this form of colitis. In this review, we discuss important pathways that are altered in IMC in mouse models and in human colon biopsy samples. This reveals a complex interplay between several types of immune cells and the gut microbiome. In addition to a mechanistic understanding, patients at risk should be identifiable before ICI therapy. Here we propose to focus on T-cell subsets that interact with bacteria after inducing epithelial damage. Especially, intestinal resident immune cells are of interest. This may lead to a better understanding of IMC and provides opportunities for prevention and management.

Keywords: colitis; immune checkpoint inhibitor (ICI); immune-related adverse events; mechanisms; treatment.

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Conflict of interest statement

FH has served on advisory boards, as speaker, or consultant for AbbVie, Celgene, Janssen-Cilag, Merck Sharp & Dohme, Takeda, Celltrion, Teva, Sandoz, and Dr Falk, and has received unrestricted grants from Dr Falk, Janssen-Cilag, and AbbVie. MH received research grants from Merck and AstraZeneca. BP received fees from advisory boards of Takeda, Bristol-Myers Squibb, Janssen, and Pfizer. BP received lecturing fees from AstraZeneca and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Mechanisms of immune checkpoint inhibitor-mediated colitis (IMC). Pro-inflammatory pathways (CTL, Th17 cells, and neutrophils) are predominantly enhanced in IMC, while anti-inflammatory pathways (Treg differentiation and IL-10 secretion) are inhibited. Other cell types, such as macrophages and ILC3s, are expected to play a role in IMC, but to which extent is unknown. This image was created with BioRender.com. CTL, Cytotoxic T-lymphocyte; CXCL, C-X-C motif chemokine ligand; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IFN, Interferon; IL, Interleukin; ILC, innate lymphoid cell; Th17, T helper 17 cell; TNF, Tumor necrosis factor; Treg, regulatory T-cell; Trm, tissue-resident memory T-cell.
Figure 2
Figure 2
Targets for treatment of immune checkpoint inhibitor-mediated colitis (IMC). Infliximab and vedolizumab are already standard of care in steroid-refractory IMC. The other agents are currently not routinely given to patients. This image was created with BioRender.com. CTL, Cytotoxic T-lymphocyte; IFN, Interferon; IL, Interleukin; JAK, Janus kinase; Th17, T helper 17 cell; TNF, Tumor necrosis factor; Treg, regulatory T-cell.
See this image and copyright information in PMC

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