Pathogenic mechanisms of immune checkpoint inhibitor (ICI)-associated retinal and choroidal adverse reactions

Purpose: To summarize and categorize postulated mechanisms of immune checkpoint inhibitor (ICI)-mediated retinal and choroidal inflammation and discuss resulting implications for evaluation and management of these adverse reactions.

Design: Targeted literature review with interpretation and perspective Methods: We performed a review of selected literature describing immune-mediated retinal and choroidal adverse reactions associated with ICI therapy, synthesizing and categorizing the likely underlying pathogenic mechanisms. Based on these mechanistic categories, we provide perspective on a rational approach to the evaluation of patients with ICI-associated inflammatory disorders of the retina and choroid.

Results: ICI-induced posterior segment adverse reactions can be categorized into three major mechanisms of unintended, targeted inflammation that share similarities to immunotherapy-related adverse events (irAEs) seen in other organ systems. In Type 1 reactions, T cell activation by ICIs can result in cross-reactivity of anti-tumor T cells with ocular tissues (Type 1a) or expansion of eye-specific T cells in predisposed individuals (Type 1b), leading to ocular inflammation that mimics known uveitic conditions. In Type 2 reactions, non-specific ocular or systemic inflammation exacerbated by ICI use can cause retinal vasculitis through a "bystander" mechanism, potentially resulting in vision-threatening vascular occlusions. Finally, in Type 3 reactions, ICI use can prompt autoantibody-mediated inflammation and/or exacerbation of paraneoplastic processes likely related to T cell driven expansion of B cell populations.

Conclusions: Although relatively uncommon, posterior segment inflammatory disorders associated with systemic ICI therapy may be vision-threatening if not identified and treated appropriately. We propose that the pathogenic mechanisms underlying these chorioretinopathies falls into three major categories involving inadvertent T cell mediated inflammation. Visual prognosis with appropriate treatment is generally favorable, but some reactions, such as longstanding exudative retinal detachments and ICI-induced occlusive retinal vasculitis, can result in permanent visual defects.