Immunopathogenesis of Immune Checkpoint Inhibitor-Induced Myositis, Myocarditis and Myasthenia Gravis Overlap Syndrome: A Mechanistic Synthesis of a Mitochondrial Autoantigen Hypothesis.

Immune checkpoint inhibitors (ICIs) have improved outcomes for cancer patients. However, they can cause toxicities called immune-related adverse events (irAEs). One serious toxicity is the myocarditis, myositis and myasthenia gravis (MMM) overlap syndrome, an inflammatory syndrome involving the heart, skeletal muscles and neuromuscular junction. Most studies on the pathogenesis of myocarditis and myositis emphasise effector CD8+ T-cell driven inflammation while myasthenia gravis (MG) is believed to be a purely antibody-driven process. This approach has several challenges: (i) lack of a unified mechanism for a pattern of inflammation involving tissues with distinct immunologic and metabolic vulnerabilities; (ii) emphasis on CD8+ T-cell driven effector mechanisms without mechanistic exploration of inciting upstream events; and (iii) the high frequency of seronegative and fulminant MG phenotypes are not fully accounted for by the current models. To address these challenges, we propose a mitochondrial autoantigen hypothesis in which tumour- and therapy-associated cellular stress releases mitochondrial damage-associated molecular patterns (DAMPs) and proteins, promoting innate immune activation and antigen presentation. These mitochondrial proteins then act as shared autoantigens across the affected tissues once immune tolerance is lifted by ICIs. We believe these mitochondrial antigens activate a tissue-agnostic adaptive immune response through CD4+ T-cell-dependent mechanisms, which then depending on local tissue factors licence a B-cell response or a CD8+ T cell response as the dominant downstream effector mechanism. This framework is supported by evidence demonstrating the immunogenicity of mitochondrial proteins, and evidence that mitochondrial proteins can enter cellular antigen presentation pathways in both non-immune- and antigen-presenting cells. The hypothesis is further supported by evidence that a pre-existing circulating systemic pre-ICI immune state with expanded CD4+ effector-memory T cells and greater T cell receptor diversity predicts severe ICI toxicity. Additional conceptual precedent for this model is provided by analogous autoantigen generation processes seen in systemic lupus, anti-neutrophil cytoplasmic antibody associated vasculitis and antimitochondrial antibody-associated myopathy. The model draws on the established tissue vulnerabilities seen in mitochondrial disorders like mitochondrial encephalopathy lactic acidosis and stroke (MELAS) and electron transport chain disorders and uses this as a biological precedent for why mitochondrial perturbation may preferentially affect myocardium, skeletal muscle and other energetically demanding tissues. This hypothesis generates falsifiable predictions for biomarker discovery and provides a plausible mechanistic rationale for current treatment strategies targeting both humoral and effector T-cell suppression in MMM syndrome.