Comparative Analysis of the Immune Profiles of Women and Men With Hepatocellular Carcinoma.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and a major global health concern, with a higher incidence in men than in women. In the era of immunotherapy, understanding sex-based immunological differences is crucial.

METHODS/PATIENTS: This study investigated sex-specific differences in anti-tumor immunity in HCC through immune profiling of liver biopsies and blood samples. A prospective cohort of 101 patients was analyzed by multiparametric flow cytometry to assess lymphocyte populations and immune checkpoint molecule expression on tumoral and nontumoral biopsies and blood samples. Then, a retrospective cohort of 56 patients was analyzed for circulating immune markers and functional assessment.

RESULTS

Our findings indicate that while overall intrahepatic immune composition was similar between sexes, female patients exhibited higher intra-tumoral PD-1high+CD8+ T cell frequency compared to men (13.3% ± 2.6% vs. 6.5% ± 0.7%, p = 0.0127), suggesting greater T cell exhaustion. Additionally, NK cells expressing CTLA-4 and ICOS were more frequent in females. Circulating immune profiles also differed, with female patients showing increased CTLA-4+ CD4+ and CD8+ T cells (p = 0.0005 and p = 0.0164) and reduced IFNγ expression, mainly in central memory CD8+ T cells.

CONCLUSIONS

These findings highlight the importance of considering sex-related differences in the context of immunotherapy for HCC and underline the need for further investigation in larger cohorts.