PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma

Abstract

The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1⁺ CXCL10⁺ macrophages and, based on cell–cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3⁺ CD8⁺ effector-memory T cells (CD8 T_EM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 T_EM preferentially differentiate into clonally-expanded PD1^- CD45RA⁺ effector-memory CD8⁺ T cells (CD8 T_EMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 T_EM remain frozen in their effector-memory state. Finally, in responders, CD8 T_EMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.

Although atezolizumab and bevacizumab have changed the treatment landscape of advanced hepatocellular carcinoma, the factors that determine responsiveness to treatment remain unclear. Using single-cell RNA sequencing, the authors identify specific macrophage and T cell subsets that are enriched in patients with durable responses.