Novel biomarkers predict immunotherapy response, side effects in HCC

A team of Singapore-based researchers has identified two blood biomarkers that not only predict clinical response to immune checkpoint inhibitors (ICIs) in hepatocellular carcinoma (HCC) patients but also the incidence of side effects from the same treatment.

The biomarkers were circulating CXCR3+CD8+ effector memory T (TEM) cells and CD11c+ antigen-presenting cells (APCs). In single-cell analyses, both were associated with response (p=0.0004 and p=0.0255, respectively), progression-free survival (p=0.00079 and p=0.0015, respectively), and immune-related adverse events (irAEs; p=0.0034 and p=0.0125, respectively) in antiprogrammed cell death 1 (anti-PD-1) therapy-treated HCC patients. [J Hepatol 2022;doi:10.1016/j.jhep.2022.03.039]

“Type-1 conventional dendritic cells were … the specific APC associated with response, while two immunosuppressive CD14+ myeloid clusters were linked to reduced irAEs,” the researchers said.

“Finally, based on predicted cell-cell communications between CXCR3+ CD8+ TEM cells and other immune cells, we found distinct pathways involving TNFR1 and TNFR2 that could be harnessed to uncouple response from irAEs in anti-PD-1 ICI therapy,” they added.

Using a preclinical mouse HCC model, the team tested several immunotherapy combinations. Treatment that combined an anti-PD-1 and an anti-TNFR2 effectively blocked a communication pathway that led to the uncoupling of the response from adverse events. This resulted in improved response to ICIs without increasing adverse events.

“While other studies have explored biomarkers for response to immune checkpoint blockade, ours is the first that found a biomarker that contributed to both the responses and adverse events resulting from the immunotherapy,” said co-senior study author Dr Valerie Chew of SingHealth’s Translational Immunology Institute (TII) in a statement.

“This allowed us to examine this biomarker further and determine if there was a way to enhance therapeutic response and, at the same time, prevent adverse events,” Chew added.

The study included 61 HCC patients from the National Cancer Centre Singapore (NCCS) and Asan Medical Center in South Korea who received intravenous nivolumab or pembrolizumab. They had their blood samples collected at baseline, before the study began, and during treatment. These samples were analysed using advanced single-cell analyses such as cytometry by time of flight (CyTOF) and single-cell RNA sequencing. 

HCC ranks as the sixth most common cancer and the fourth leading cause of cancer mortality worldwide. ICIs have shown promise in the treatment of HCC, although their use yields modest response rates (15–18 percent) and the incidence of higher-grade treatment-induced irAEs is quite common. [CA Cancer J Clin 2018;68:394-424; Lancet Oncol 2022;23:77-90; J Clin Oncol 2020;38:193-202]

Commenting about the clinical implications of the current study, the researchers said that aside from identifying a new combination immunotherapy for HCC that enhances response without exacerbating adverse events, the findings provide “an in-depth understanding of the immunological mechanisms behind response and adverse events in patients with HCC treated with ICI.”

“We are excited that our findings have presented a novel treatment pathway and are now exploring this combination and aim to bring this new therapy to patients with primary liver cancer,” said co-senior study author Professor David Tai of the NCCS.