Journal for immunotherapy of cancer · 2025
HLA-A*01:01-B*08:01-C*07:01 is linked to early-onset immune checkpoint inhibitor-induced myositis and myocarditis.
СтатьяМногоцентровое исследованиеНазвание и аннотация: Перевод в очереди
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Müller-Jensen Leonie, Flatz Lukas, Hasan Ali Omar, Mohr Raphael, Lachmann Nils, Mödl Lukas, Endres Matthias, Boehmerle Wolfgang, Huehnchen Petra
Аннотация
BACKGROUND: Immune-related myotoxicity (irM), including irMyocarditis and irMyositis, is a severe complication of immune checkpoint inhibitors (ICIs). Markers to identify patients at risk are missing. In this retrospective multicenter cohort study, we aimed to determine whether specific human leukocyte antigen (HLA) variants are associated with irM.
METHODS: Twenty patients with irMyocarditis and/or irMyositis (median age (IQR), 67 (60-73) years; 7/20 female) and 60 cancer controls (CC) without immune-related adverse events (median age (IQR), 68 (62-74) years; 26/60 female) presenting to Charité - Universitätsmedizin Berlin, Germany, or Kantonsspital St. Gallen, Switzerland, between September 2017 and June 2024, were included. As a second control cohort, we used HLA data from a historic dataset of 5.1×10⁶ German healthy donors (G-HD). Allele frequencies (AF) of two-field HLA types were compared between patients with irM, CC, and G-HD using logistic regression and two-sided z-tests of odds ratios (OR).
RESULTS: Comparison of single HLA AF between patients with irM and G-HD revealed moderate associations for irM with B*07:02 (OR 2.29; 95% CI 1.12 to 4.69; p=0.023), B*40:01 (OR 2.75; 95% CI 1.08 to 7.02; p=0.035), C*03:04 (OR 2.46; 95% CI 1.09 to 5.56; p=0.031), DPB1*04:02 (OR 2.37; 95% CI 1.16 to 4.85; p=0.018), and DQB1*06:02 (OR 2.28; 95% CI 1.12 to 4.67; p=0.024). No statistically significant differences were observed between patients with irM and CC. By contrast, multi-allelic HLA analysis identified a strong association between HLA-A*01:01-B*08:01-C*07:01, a component of the 8.1 ancestral haplotype (8.1 AH), and early-onset irM (onset ≤3 months after ICI initiation, n=11), compared with G-HD (22.7% vs 7.6%; OR 3.59; 95% CI 1.33 to 9.74; p=0.012) and CC (22.7% vs 7.5%; OR 3.62; 95% CI 1.09 to 12.12; p=0.036). Intriguingly, early-onset irM was linked to higher troponin T levels compared with late-onset irM (p=0.005, Cohen's r=0.63).
CONCLUSIONS: Our results provide first evidence that early-onset irM with myocardial injury is linked to HLA-A*01:01-B*08:01-C*07:01, a component of the 8.1 AH, which is associated with various autoimmune diseases including idiopathic myopathies. If validated in larger cohorts, pretreatment screening for HLA-A*01:01-B*08:01-C*07:01 may help identify patients at risk of early-onset and severe irM.
METHODS: Twenty patients with irMyocarditis and/or irMyositis (median age (IQR), 67 (60-73) years; 7/20 female) and 60 cancer controls (CC) without immune-related adverse events (median age (IQR), 68 (62-74) years; 26/60 female) presenting to Charité - Universitätsmedizin Berlin, Germany, or Kantonsspital St. Gallen, Switzerland, between September 2017 and June 2024, were included. As a second control cohort, we used HLA data from a historic dataset of 5.1×10⁶ German healthy donors (G-HD). Allele frequencies (AF) of two-field HLA types were compared between patients with irM, CC, and G-HD using logistic regression and two-sided z-tests of odds ratios (OR).
RESULTS: Comparison of single HLA AF between patients with irM and G-HD revealed moderate associations for irM with B*07:02 (OR 2.29; 95% CI 1.12 to 4.69; p=0.023), B*40:01 (OR 2.75; 95% CI 1.08 to 7.02; p=0.035), C*03:04 (OR 2.46; 95% CI 1.09 to 5.56; p=0.031), DPB1*04:02 (OR 2.37; 95% CI 1.16 to 4.85; p=0.018), and DQB1*06:02 (OR 2.28; 95% CI 1.12 to 4.67; p=0.024). No statistically significant differences were observed between patients with irM and CC. By contrast, multi-allelic HLA analysis identified a strong association between HLA-A*01:01-B*08:01-C*07:01, a component of the 8.1 ancestral haplotype (8.1 AH), and early-onset irM (onset ≤3 months after ICI initiation, n=11), compared with G-HD (22.7% vs 7.6%; OR 3.59; 95% CI 1.33 to 9.74; p=0.012) and CC (22.7% vs 7.5%; OR 3.62; 95% CI 1.09 to 12.12; p=0.036). Intriguingly, early-onset irM was linked to higher troponin T levels compared with late-onset irM (p=0.005, Cohen's r=0.63).
CONCLUSIONS: Our results provide first evidence that early-onset irM with myocardial injury is linked to HLA-A*01:01-B*08:01-C*07:01, a component of the 8.1 AH, which is associated with various autoimmune diseases including idiopathic myopathies. If validated in larger cohorts, pretreatment screening for HLA-A*01:01-B*08:01-C*07:01 may help identify patients at risk of early-onset and severe irM.