Association of HAMP Expression and CD8+ T-Cell Infiltration With Atezolizumab-Bevacizumab Response in Hepatocellular
Shun Nakamura1, Yuki Murakami2, Yusuke Oshima1,2,3,4
1Department of Gastroenterological and Pediatric Surgery, Faculty of Medicine Oita University Yufu Oita Japan.
Aim:
Atezolizumab combined with bevacizumab is the standard first-line therapy for unresectable hepatocellular carcinoma; however, predictive biomarkers of therapeutic response remain undefined. We aimed to identify molecular features associated with therapeutic efficacy to develop personalized treatment strategies.
Methods:
Transcriptomic analyses were performed using public RNA-sequencing datasets of patients with hepatocellular carcinoma receiving anti-PD-L1-based therapy, comparing responders (complete response/partial response) with non-responders (stable disease/progressive disease). Differentially expressed genes and enriched pathways were identified using integrated differential expression and pathway analysis. For validation, RNA-sequencing was performed on institutional tumor samples (n = 6) underwent. Immunohistochemistry was performed on resected specimens (n = 9) to evaluate CD8+ tumor-infiltrating lymphocytes and hepcidin protein expression encoded by the HAMP gene. Group comparisons for the pre-specified immunohistochemistry endpoints were analyzed using exact Wilcoxon rank-sum tests with multiplicity control (Holm adjustment).
Results:
Analysis of public datasets revealed distinct expression profiles in responders, enriched in immune-related and chemokine signaling pathways. Candidate genes, including HAMP, TAT, and HRG, were upregulated in responders. In institutional samples, HAMP expression was significantly higher in preoperatively treated tumors (p = 0.001). Immunohistochemistry demonstrated greater CD8+ tumor-infiltrating lymphocyte density (median 36.6 vs. 5.0 cells/high-power field; exact Wilcoxon p = 0.032) and higher HAMP immunoreactive scores (median 4 vs. 0.5; p = 0.032) in responders than in non-responders.
Conclusions:
Upregulation of HAMP and hepcidin protein expression, together with increased CD8+ T-cell infiltration, was associated with a favorable response to atezolizumab-bevacizumab in patients with hepatocellular carcinoma. HAMP may serve as a component of a composite biomarker predictive of therapeutic sensitivity, warranting validation in larger, multi-institutional cohorts.
