Immune-related adverse events after immune check point inhibitors: Understanding the intersection with autoimmunity

Abstract

Immune checkpoint inhibitor therapies act through blockade of inhibitory molecules involved in the regulation of T cells, thus releasing tumor specific T cells to destroy their tumor targets. However, immune checkpoint inhibitors (ICI) can also lead to a breach in self-tolerance resulting in immune-related adverse events (irAEs) that include tissue-specific autoimmunity. This review addresses the question of whether the mechanisms that drive ICI-induced irAEs are shared or distinct with those driving spontaneous autoimmunity, focusing on ICI-induced diabetes, ICI-induced arthritis, and ICI-induced thyroiditis due to the wealth of knowledge about the development of autoimmunity in type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. It reviews current knowledge about role of genetics and autoantibodies in the development of ICI-induced irAEs and presents new studies utilizing single-cell omics approaches to identify T-cell signatures associated with ICI-induced irAEs. Collectively, these studies indicate that there are similarities and differences between ICI-induced irAEs and autoimmune disease and that studying them in parallel will provide important insight into the mechanisms critical for maintaining immune tolerance.

Keywords: Hashimoto's thyroiditis; autoimmunity; immune checkpoint inhibitor therapy; immune related adverse events; rheumatoid arthritis; type 1 diabetes.

Figure 1. Factors promoting the development of autoimmunity.

Autoimmune diseases develop over time and due to a combination of factors. Individuals are born with genetic risk, environmental factors are thought to trigger the loss of tolerance and expansion of autoreactive T and B cells until finally due to additional triggers or immune experience inflammation leads to clinical disease.

Figure 2. Mechanisms involved in the maintenance and loss of immune tolerance

(A) Mechanisms maintaining self-tolerance; autoreactivity is regulated at multiple points in the development of B and T cells. Central or deletional tolerance, B cell help provided by Tfh, blunted of responses to activation and suppression by Treg. Co-inhibitory receptor involvement is shown by gold stars in the diagram. (B) Impact of immune checkpoint inhibitor therapy on self-tolerance. Regulatory pathways inhibited by ICI therapy are shown by an “X”. Created using BioRender.com