|Biomarkers to Predict Response to Immunotherapy for Refractory Hepatocellular Carcinoma|
|Date||Modified Date : 2022.03.21 (Create Date : 2022.03.16)|
Biomarkers to Predict Response to Immunotherapy for Refractory Hepatocellular Carcinoma
A team led by Professor Jason Kyungha Sa (co-first author) from Korea University Graduate School of Medicine identified the molecular properties that determine the response to immune checkpoint inhibitors in liver cancer patients.
Hepatocellular carcinoma accounts for the majority of primary liver malignancy and is the fourth leading cause of cancer-related mortalities worldwide and it is known to have a high incidence in Asia.
Pembrolizumab, an immune checkpoint inhibitor, has been approved as a second-line treatment for hepatocellular carcinoma, but the identification of reliable biomarkers to predict the response to the treatment remained a major challenge.
The research team conducted an integrated multi-omics analyses of 60 hepatocellular carcinoma patients who received pembrolizumab to identify distinct genomic correlates that distinguish responders from non-responders.
Patients’ cancer tissue specimens were collected and genomic properties were characterized such as tumor microenvironment by assessing the results from whole-exome sequencing (WES), RNA and single-cell RNA sequencing.
This is to identify the primary cause of different effects of immunotherapy during treatment and to distinguish molecular biomarkers that can help identify those who are likely to benefit from the therapy.
The research team examined the differences by observing the patients' treatment process based on the results of high-precision analysis of the patients' genome. According to the research team, six out of the 60 hepatocellular carcinoma patients who received immunotherapy demonstrated partial response to the treatment, with an overall response rate of 10%. Clinical pathological analysis confirmed that female gender, PD-L1 positivity, and low neutrophil-to-lymphocyte ratio (NLR) were contributing factors to immunotherapy response.
On the other hand, somatic mutations in CTNNB1 and genomic amplifications in MET were found only in non-responders. Transcriptional profiles through RNA sequencing identified that responders demonstrated T cell receptor (TCR) signaling activation, indicating increased levels of T cell cytotoxicity induced response to immunotherapy.
In single-cell sequencing from 10 pre- and post-treatment peripheral blood mononuclear cells (PBMCs), patients who achieved a partial response or stable disease exhibited immunological shifts toward cytotoxic CD8+ T cells. Conversely, non-responders showed an increased number of both CD14+ and CD16+ monocytes and activation of neutrophil-associated pathways. Taken together, HCC patients with infiltration of cytotoxic T cells, along with increased active circulating CD8+ T cells and down-regulation of neutrophil-associated markers, significantly benefited from immunotherapy.
Professor Sa said, "The results of this study will help discover the next generation of immunotherapeutics for cancer patients who do not respond to the existing treatment modalities."
The study entitled "Hepatocellular carcinoma patients with high circulating cytotoxic T cells and intra-tumoral immune signature benefit from pembrolizumab: results from a single-arm phase 2 trial" was conducted along with Samsung Medical Center with support from the Research-Oriented Hospital Development R&D Project of the Ministry of Health and Welfare, and was published in the January issue of the international renowned journal, Genome Medicine (IF 11.117).