PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma
Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Bram Boeckx, Rogier Schepers, Thomas Van Brussel, Ingrid Arijs, Aurelie Mechels, Ayse Bassez, Francesca Lodi, Joris Jaekers, Halit Topal, Baki Topal, Orian Bricard, Junbin Qian, Eric Van Cutsem, Chris Verslype, Diether Lambrechts, Jeroen Dekervel
Abstract
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.