The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in a subset of patients. Using single-cell profiling, we characterized the intra-tumoural and peripheral immune context of aHCC patients treated with atezo/bev. Tumours with durable response were enriched for PDL1-expressing CXCL10+ macrophages and, based on cell-cell interaction analysis, expressed high levels of CXCL9/10/11 to potentially attract peripheral CXCR3+ effector-memory T-cells (CD8 T_EM) into the tumour. Based on T-cell receptor sharing and pseudotime trajectory analysis, we found CD8 T_EM to preferentially differentiate into clonally-expanded PD1-negative, CD45RA effector-memory CD8 T-cells (CD8 T_EMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 T_EM remained frozen in their effector-memory state. Finally, in responders, CD8 T_EMRA displayed a high degree of T-cell receptor sharing with blood, consistent with their patrolling activity. Here, we shed light on the mechanisms of response to atezo/bev in aHCC.

PD-1^- CD45RA⁺ effector-memory CD8 T cells and CXCL10⁺ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma. Cappuyns et al. – 2023 – Nature Communications

Data Availability

Raw sequencing reads of the scRNAseq, scTCRseq and Totalseq experiments have been deposited under restricted access in the European Genome-phenome Archive (EGAS00001007547). Requests for accessing raw sequencing reads will be reviewed by the UZLeuven-VIB data access committee. Any data shared will be released via a Data Transfer Agreement that will include the necessary conditions to guarantee protection of personal data (according to European GDPR law)

Alternatively, a download of the read count data of both tumor biopsies and peripheral blood samples necessary to reproduce the published results, is more readily available form this website. Corresponding meta data regarding timepoint (week 0, week 3, week 6), treatment (atezolizumab+bevacizumab versus anti-PD(L)1 monotherapy (ICP) versus tyrosine-kinase inhibitor (TKI)) and response (responders versus non-responder) are provided. In accordance with GDPR regulations, please note that individual sample identifiers used for this data deposit are different from, and cannot be tracked back, to the patient identifiers used throughout the manuscript.