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.