Toxicity in the era of immune checkpoint inhibitor therapy

Abstract

Immune checkpoint inhibitors (ICIs) reinvigorate anti-tumor immune responses by disrupting co-inhibitory immune checkpoint molecules such as programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4). Although ICIs have had unprecedented success and have become the standard of care for many cancers, they are often accompanied by off-target inflammation that can occur in any organ system. These immune related adverse events (irAEs) often require steroid use and/or cessation of ICI therapy, which can both lead to cancer progression. Although irAEs are common, the detailed molecular and immune mechanisms underlying their development are still elusive. To further our understanding of irAEs and develop effective treatment options, there is pressing need for preclinical models recapitulating the clinical settings. In this review, we describe current preclinical models and immune implications of ICI-induced skin toxicities, colitis, neurological and endocrine toxicities, pneumonitis, arthritis, and myocarditis along with their management.

Keywords: immune checkpoint; immune related adverse events; immunotherapy; preclinical model; treatment.

Figure 1

(A) Immune checkpoints in maintaining peripheral tolerance. 1). T cells (CD4 or CD8) are activated by the presentation of antigens on major histocompatibility complex (MHC)-I and II by antigen presenting cells to T cell receptors (TCRs). To regulate T cell activation and prevent their hyper- responsiveness, inhibitory receptors such as PD-1 and CTLA-4 interact with their respective ligands such as PDL-1 and CD80/CD86 to impose negative regulatory signals on T cells. T regulatory cells also control T cell responses through the consumption of IL-2, which is secreted by T cells during their activation. This process will lead to 2). moderate T cell expansion and migration to the tissues, lessening 3). inflammation in targeted tissues. (B) Immune checkpoint blockade (ICB) may break the peripheral tolerance. 1). Blocking inhibitory receptors (PD-1 or CTLA-4) using αPD1 and αCTLA4 antibody induce a prolonged T cell activation and may hinder regulatory T cells from controlling T cell activation and responses. This process can lead to 2). high clonal expansion and migration of T cells to targeted tissues, resulting in 3). high grade inflammation and cause significant tissue damage. Systemic ICB administration may also drive the expansion of tissue resident cells or non-specific immune cells residing in dormant states in the corresponding tissues, contributing to more inflammation and tissue damage. Created with BioRender.com.

Figure 2

Cellular and molecular players involved in ICI-induced irAEs. Schematic representation of immune cell populations and effector molecules which are frequently enhanced in each specified iRAE. Common cell populations implicated in ICI-induced iRAEs are CD8+ T cells, TH1, and TH17 cells. Additionally, B cells, NK cells, and myeloid cell populations have also been implicated in specific iRAEs. Prominent effector molecules that are increased in ICI-induced iRAEs are IFNγ, TNFα, IL-6 and IL-17. Auto-antibodies and complement molecules can also play a role in specific iRAEs. Created with BioRender.com.