Abstract PR03: Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing

Abstract

Abstract The novel combination of atezolizumab/bevacizumab has demonstrated unprecedented response rates in a subgroup of advanced hepatocellular carcinoma (aHCC) patients. In order to understand why only a subset of aHCC patients respond to immunotherapy targeting the PD-1/PD-L1 axis, we subjected pre-treatment tissue biopsies from 31 aHCC patients, with mainly non-viral etiologies, to simultaneous single-cell transcriptome (scRNAseq) and T-cell receptor (scTCRseq) sequencing, providing an integrative view of the tumor-microenvironment of aHCC (n=91 169 cells). The therapeutic targets, PD-1 and PD-L1 are expressed in tumor-infiltrating T- cells versus myeloid cells and tumor cells, respectively. Myeloid cells in tumors responding to immunotherapy (according to mRECIST) express significantly higher levels of PD-L1 (p=0.014) compared to non-responders and this is driven by pro-inflammatory PD-L1 expressing CXCL10+ macrophages, involved in T-cell recruitment. In contrast, non-responding tumors are infiltrated by immature CX3CR1+ macrophages and CCR2+ ‘monocyte-like’ macrophages (p=0.009 and p=0.01, respectively). Interestingly, the composition of tumor-infiltrating T-cells did not differ significantly between patient groups. However, responding tumors were characterized by a more clonal baseline T-cell receptor repertoire (p=0.007). Single-cell T-cell receptor sequencing revealed that this clonality was present in activated, effector T-cells, while non-responders had a higher proportion of non-clonal T-cells (p=0.01) concentrated within naïve and memory-like T-cell phenotypes. In conclusion, this is the first and largest aHCC cohort to correlate single-cell sequencing data with clinical outcomes. Prior to treatment, differences in abundancy and ligand expression in small clusters of immune cells as well as difference in baseline T-cell clonality drive response to checkpoint inhibition in aHCC. Citation Format: Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Chris Verslype, Eric Van Cutsem, Diether Lambrechts, Jeroen Derkervel. Pretreatment immune cell composition and checkpoint ligand expression define the response to immunotherapy in advanced HCC: a study using single-cell sequencing [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PR03.