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Research Article: LAG3-centered multiplex immune profiling as a prognostic biomarker in hepatocellular carcinoma patients receiving Anti-PD-1 antibodies plus lenvatinib therapy

Date Published: 2026-07-01

Abstract:
This study aims to investigate the characteristics and functional status of the lymphocyte-activation gene-3 (LAG-3), cluster of differentiation 8 (CD8), programmed cell death protein-1 (PD-1) immune microenvironment in tumor tissues of hepatocellular carcinoma (HCC) patients and evaluate their value as prognostic biomarkers for the efficacy of combination of anti-PD-1 antibodies with Lenvatinib. This retrospective study collected clinical data from 77 patients with hepatocellular carcinoma who received Lenvatinib plus anti-PD-1 antibodies at the Department of Oncology, Nanjing Drum Tower Hospital between January 2018 and June 2023. Following combination therapy with Lenvatinib and anti-PD-1 antibodies, 1 patient achieved complete response (CR), 23 achieved partial response (PR), 39 achieved stable disease (SD), and 14 achieved progressive disease (PD). Age stratification (<60 years vs ?60 years), cirrhosis status, and Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1) were statistically associated with treatment response in HCC patients. Multivariate Cox regression analysis revealed that the high pan-immune-inflammation value (PIV) expression group [ Hazard ratio (HR)=9.239, 95% confidence interval (CI): 1.731-49.310, P = 0.009], the low LAG-3 + cell counts group (HR = 0.190, 95% CI: 0.042-0.857, P = 0.031), the low CD8 + LAG-3 + cell density group (HR = 0.198, 95% CI: 0.041-0.962, P = 0.045), the low area proportion of CD8 + LAG-3 + cell group (HR = 5.203, 95% CI: 1.093-24.770, P = 0.038) were independent prognostic risk factors for overall survival (OS) in patients receiving Lenvatinib plus anti-PD-1 antibodies. Independent prognostic risk factors for progression-free survival (PFS) in treated patients included the low albumin (ALB) level group (HR = 0.196, 95% CI: 0.042-0.923, P = 0.039) and the high neutrophil-to-lymphocyte ratio (NLR) group (HR = 2.894, 95% CI: 1.076-7.785, P = 0.035). Our study proposes that LAG-3 serves as a potential prognostic factor for identifying survival benefits from Lenvatinib plus anti-PD-1 antibodies in hepatocellular carcinoma patients.

Introduction:
Hepatocellular carcinoma (HCC) is the sixth most commonly diagnosed malignancy and the fourth leading cause of cancer-related mortality worldwide ( 1 ). As the predominant subtype of primary liver cancer, HCC typically develops in the context of chronic liver disease. Well-established etiological risk factors include chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, alcohol-associated liver disease, and non-alcoholic steatohepatitis (NASH) ( 2 ). The clinical onset of HCC is usually insidious;…

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