Baseline Circulating and Tumor γδ T Cells and Early Circulating CD8+PD-1+ Expansion Predict Response to Atezolizumab–Bevacizumab in HCC

PURPOSE: We aimed to identify circulating and tumor immune features predictive of oncologic outcomes under atezolizumab-bevacizumab (AtezoBev) therapy for hepatocellular carcinoma. EXPERIMENTAL DESIGN: We conducted a prospective study in 31 patients treated with first-line AtezoBev, integrating sequential peripheral blood mononuclear cell (PBMC) immunophenotyping, cytokine profiling, and whole-blood RNA sequencing (RNA-seq). Tumor RNA-seq data from the clinical trials (GO30140/IMbrave150; 209 AtezoBev- and 58 sorafenib-treated patients), together with 163 tumor samples of patients with microsatellite instability-high (MSI-H) colorectal cancer treated with immunotherapy, were used to assess the predictive value of immune signatures. RESULTS: Based on the PBMC analysis at baseline (87% of male, age 65 years, and 65% of Barcelona Clinic Liver Cancer stage C), high baseline circulating γδ T cells were 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 cell 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 with sorafenib. In MSI-H colorectal cancer treated with immunotherapy, a high γδ T cell signature was associated with longer PFS (P = 0.034). An increase in circulating CD8+TIGIT+ T cells was associated with shorter PFS (P = 0.04), whereas an increase in CD8+PD-1+ T cells correlated with longer PFS (P = 0.03). Paired transcriptomic analyses confirmed an early induction of T cell-associated interferon (IFN) γ signaling at 3 weeks after the first injection of AtezoBev in patients who 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. An early increase in circulating CD8+TIGIT+ T cells was associated with treatment resistance.