Evolutionary divergence of the HLA-B genotype as a predictor of immune checkpoint inhibitor (ICI) therapy efficacy in hepatobiliary cancers.

4107 Background: The role of human leukocyte antigen class I (HLA-I) molecules in shaping the immune response to immune checkpoint inhibitors (ICIs) has been recognized in several solid malignancies. However, the prognostic significance of HLA-I characteristics in hepatobiliary cancers remains poorly understood. Methods: Patients with advanced hepatocellular carcinoma (aHCC) and biliary tract cancer (aBTC) receiving ICI-based therapy were prospectively enrolled (NCT03892577). Retrospective analyses were performed to evaluate the association between HLA-I evolutionary divergence (HED), HLA-I genotype, and HLA-I heterozygosity with clinical outcomes. HLA-I genotyping was conducted using germline DNA from peripheral blood, and HED was quantified based on the Grantham distance metric, which measures evolutionary divergence between HLA-I alleles. Patients were stratified into high and low HED groups using the 25th percentile as the cutoff. Results: A total of 118 patients (41 with aHCC and 77 with aBTC) were included in the analysis. High HED at the HLA-B genotype was significantly associated with improved overall survival (OS) in patients treated with ICIs (p < 0.05). Specifically, in aHCC patients, the median OS was 17.43 (95% confidence interval, 17.43-NE) months in the HLA-B HED high group compared to 7.83 months (95% confidence interval, 4.13-NE) in the HLA-B HED low group (p < 0.05). Similarly, in aBTC patients, the median OS was 12.7 (95% confidence interval, 9.07-20.90) months versus 9.8 (95% confidence interval, 6.40-13.5) months, respectively (p < 0.05). In contrast, HED at the HLA-B genotype did not exhibit a significant association with progression-free survival. Conclusions: This study demonstrates that the evolutionary divergence of the HLA-B genotype may serve as a prognostic biomarker for ICI therapy in hepatobiliary cancers. High HED at HLA-B is associated with improved OS, underscoring the potential role of HLA-I genetic diversity in modulating therapeutic response to ICIs. These findings provide a foundation for further investigations into HLA-mediated mechanisms underlying ICI efficacy in hepatobiliary cancers. More patients will be enrolled to validate the conclusions. Clinical trial information: NCT03892577 .