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 <i>NLRC5</i>, 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 <i>NLRC5</i> 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 (<i>NLRC5Pro191Leu</i>) 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 <i>NLRC5</i> variant, studying expression of <i>NLRC5</i> and select downstream target genes, before and after stimulation with interferon-γ.We validated the higher prevalence of <i>NLRC5Pro191Leu</i> 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 <i>NLRC5Pro191Leu</i> 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 <i>NLRC5</i> (p=0.007), <i>TAP1</i> (p=0.0002), <i>B2M</i> (p=0.0005), <i>HLA-G</i> (p=0.04), <i>PSMB8</i> (p=0.03) and <i>PSMB9</i> (p=0.01) in <i>NLRC5Pro191Leu</i> cells stimulated with interferon-γ compared with <i>NLRC5^WT</i> cells. A similar trend was observed for <i>HLA-A</i> (p=0.09).We confirm the significantly higher prevalence of the <i>NLRC5Pro191Leu</i> 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 <i>NLRC5</i> 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 <i>NLRC5Pro191Leu</i> variant requiring ICIs.