Factors that increase class I MHC expression may contribute to the development of immune checkpoint inhibitor-induced diabetes.

Immune checkpoint inhibitors (ICIs) have improved survival of patients with cancer, yet they pose risks of immune-related adverse events (irAEs). ICI-induced insulin-dependent diabetes mellitus (ICI-DM) is a life-threatening and life-altering irAE. Previously, we reported a high incidence of a germline missense variant in , a key class I transcription activator, among patients with ICI-DM compared with similarly treated patients who did not develop ICI-DM. Our purpose was to validate this finding in additional ICI-treated patients and study effects of the variant on expression of class I major histocompatibility complex (MHC) antigen presentation genes.We assessed the prevalence of the C>T missense variant at chr16:57 025 515 () in germline DNA from an additional 33 patients with ICI-DM and in patients with ICI-induced colitis (n=15), ICI-induced hypothyroidism (n=19) and ICI-induced hypophysitis (n=17). The 1,000 Genomes Project was used for comparison. We assessed peripheral blood mononuclear cells from 16 individuals with or without the variant, studying expression of and select downstream target genes, before and after stimulation with interferon-γ.We validated the higher prevalence of in a non-overlapping cohort of patients with ICI-DM compared with the general population (51.5% vs 12.8%, p<0.0001). The prevalence of in ICI-induced colitis or thyroiditis patients did not significantly differ from the general population, while the prevalence in ICI-induced hypophysitis was somewhat higher (21.6%, p=0.048). We found greater increases in messenger RNA expression of (p=0.007), (p=0.0002), (p=0.0005), (p=0.04), (p=0.03) and (p=0.01) in cells stimulated with interferon-γ compared with cells. A similar trend was observed for (p=0.09).We confirm the significantly higher prevalence of the variant in patients with ICI-DM relative to the general population. This abundance appears to be unique to patients who develop ICI-DM or hypophysitis on ICIs, underscoring its potential involvement in the pathogenesis of these endocrinopathies. The effects of this variant on class I MHC regulators suggest a mechanistic connection between the variant and development of ICI-DM. Further work is warranted to determine whether class I MHC molecules can be modulated in patients with the variant requiring ICIs.