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

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.