Baseline circulating and tumor γδ T cells and early circulating CD8⁺PD1⁺ expansion predict response to Atezolizumab-bevacizumab in HCC

BACKGROUND: We aimed to identify circulating and tumor immune features predictive of oncological outcomes under Atezolizumab-Bevacizumab (AtezoBev) therapy for hepatocellular carcinoma (HCC). METHODS: We conducted a prospective study in 31 patients treated with first-line AtezoBev, integrating sequential PBMC immunophenotyping, cytokine profiling and whole-blood RNA sequencing. Tumor RNA-sequencing data from clinical trial (GO30140/IMbrave150, 209 AtezoBev and 58 sorafenib-treated patients), together with 163 MSI-H colorectal cancer (CRC) treated by immunotherapy were used to assess the predictive value of immune signatures. RESULTS: Based on PBMC analysis at baseline (87% of male, age 65 years and 65% of BCLC-C), high baseline circulating γδ T-cells was associated with disease control (p=0.006) and longer progression free survival (PFS) (p=0.02). In tumor RNA-seq, a high intratumoral γδ T signature was also associated with higher response (p<0.01), longer PFS (p<0.001), and longer overall survival (p=0.003) exclusively in AtezoBev-treated patients, but not for those treated by sorafenib. In MSI-H CRC treated by immunotherapy, a high γδ T-cell signature was associated with longer PFS (p=0.034). An increase in circulating CD8⁺TIGIT⁺ cells was associated with shorter PFS (p=0.04), whereas an increase in CD8⁺PD-1⁺ cells correlated with longer PFS (p=0.03). Paired transcriptomic analyses confirmed an early induction of T cell-associated interferon-γ signaling at 3 weeks after the first injection of AtezoBev in patients that experienced response. CONCLUSIONS: High baseline circulating and tumor γδ T cells and early circulating CD8⁺PD-1⁺ T Cell expansion were associated with better outcome under AtezoBev. Early increase in circulating CD8⁺TIGIT⁺ cells was associated with treatment resistance.