Enrichment of the germline <i> NLRC5 ^Pro191Leu </i> variant in patients with immune checkpoint inhibitor–induced hepatitis.

Abstract

2660 Background: Immune checkpoint inhibitor–induced hepatitis (ICI-hepatitis) is a clinically significant immune-related adverse event (irAE) that may require treatment interruption and immunosuppressive therapy. Predictors of susceptibility to irAEs remain poorly defined. NLRC5 is a key regulator of MHC class I antigen presentation and CD8⁺ T-cell–mediated immune activation. We previously identified a germline missense variant at the NLRC5 gene ( NLRC5 Pro191Leu ) that is associated with ICI-related endocrinopathies, and increased expression of downstream genes involved in antigen presentation. Our purpose was to determine whether the variant has a broader role in immune-related toxicity. Methods: We evaluated the prevalence and clinical associations of the germline NLRC5 Pro191Leu variant in patients with grade ≥2 ICI-hepatitis. Sanger sequencing was performed to assess the NLRC5 Pro191Leu (rs74439742) germline variant. Hepatitis severity was graded according to CTCAE criteria. Clinical data included irAE co-occurrence, duration of corticosteroid therapy, and requirement for additional immunosuppression. Variant prevalence was compared with the general population using data from the 1000 Genomes Project. Results: Among 39 patients with ICI-hepatitis, the cohort was predominantly composed of patients with metastatic melanoma receiving ipilimumab plus nivolumab. The variant was significantly enriched in the ICI-hepatitis cohort compared with the general population (30.0% vs 12.8%; p = 0.007, odds ratio [OR] = 2.9). Variant carriers also more frequently developed co-occurring endocrine irAEs, particularly thyroid dysfunction and hypopituitarism. Conversely, co-occurrence of hepatitis and colitis was more frequent among wild-type patients (p = 0.06, OR = 7.6), suggesting distinct immunopathogenic toxicity patterns. The severity of hepatitis was assessed by a composite outcome of maximal grade 4 hepatitis and prolonged steroid use (≥120 days). Variant carriers showed a trend toward increased hepatitis severity that did not reach statistical significance (Fisher’s exact p = 0.06; OR = 4.9). Conclusions: Germline NLRC5 Pro191Leu is significantly more common in patients who develop ICI-hepatitis than in the general population and is associated with distinct immune-related toxicity patterns. This suggests that host genetic factors may inform toxicity surveillance and early management strategies. Larger multi-center studies are needed to validate these observations and define the clinical utility of NLRC5 Pro191Leu as a predictor of immune-related toxicity risk. Prevalence of NLRC5 Pro191Leu variant in the ICI-hepatitis cohort. Group NLRC5 WT, n (%) NLRC5Pro191Leu , n (%) ICI-hepatitis cohort (n=39) 27 (70.0) 12 (30.0) Odds ratio 2.9 p value 0.007 General population (1000 Genomes Project) (n=694) 605 (87.2) 89 (12.8)