In brief

Using a multimodal approach that included sequencing and immunoassays, researchers show that a higher tumour mutation burden and specific gene mutations correlate with better treatment outcomes for patients with hepatocellular carcinoma.

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Turning cold tumours into hot targets

4 Apr 2024

Researchers identify predictive immune ‘signatures’ in liver cancer patients that can help tailor and improve the success rates of combined immunotherapy and radiotherapy.

The immune system is naturally programmed to identify and fight off cancer cells. However, ‘cold’ tumours, such as hepatocellular carcinoma (HCC)—a form of liver cancer—either lack the signals that alert the immune system or create a suppressive environment that inhibits the immune response. This makes such tumours notoriously difficult to treat with therapies that depend on the immune system's natural cancer-fighting abilities.

To deal with the cold tumours seen in HCC, some experts are turning to Y90 radioembolisation: a treatment where radioactive beads are injected into the blood vessels that feed a tumour, with the goal of delivering targeted radiation therapy that avoids healthy liver tissue.

“Y90 radioembolisation can turn a tumour from ‘immune cold’ to ‘immune hot’ so that patients have a higher chance of benefiting from immunotherapy,” said Joe Yeong, a Group Leader at A*STAR’s Institute of Molecular and Cell Biology (IMCB). A recent Phase II clinical trial has corroborated the increased efficacy of this approach in HCC patients, Yeong added.

To spearhead efforts in enhancing the effectiveness of a combined immunotherapy (nivolumab) and Y90 radioembolisation treatment for treating HCC, Yeong worked with colleagues from A*STAR; the National Cancer Centre Singapore; Singapore General Hospital; National University of Singapore; University of Cologne, Germany; and Guangzhou International Bio Island, China.

Aiming to identify the patients that stand to benefit most from this therapeutic strategy, the researchers performed whole exome sequencing, RNA-sequencing and immunoassays on blood samples from 33 patients enrolled in the Phase II trial. They discovered that those with a higher tumour mutation burden and NCOR1 gene mutations, which influence gene regulation, were more likely to respond, as proven by robust inflammatory markers and a proliferation of immune cells such as macrophages.

Conversely, the patients for whom treatment was ineffective frequently showed chromosomal alterations and enhanced cellular growth processes, with many exhibiting Kaya_P2, a molecular signature specific to Asian genomes.

This led the team to hypothesise that the combination therapy's efficacy may vary across ethnicities. “We are working with an oncology group based in Spain to combine data from two clinical trials, allowing us to compare European and Asian cohorts to generate more convincing markers,” Yeong said.

Identifying these predictive markers offers a promising path to refining patient stratification and choosing more appropriate treatments, potentially doubling the response rate from immunotherapy alone to that achieved with the combination therapy.

“The next step is to add in longitudinal immune profiles or other biomarkers as we head towards a multi-omics era for personalised treatments against cancer,” said Yeong.

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), Bioinformatics Institute (BII), Institute of Molecular and Cell Biology (IMCB) and the Singapore Immunology Network (SIgN).

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Kaya, N.A., Tai, D., Lim, X., Lim, J.Q., Lau, M.C., et al. Multimodal molecular landscape of response to Y90-resin microsphere radioembolization followed by nivolumab for advanced hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer 11 (8), e007106 (2023). | article

About the Researchers

Joe Yeong’s main research focus is to understand and overcome the resistance of immune checkpoint blockade immunotherapy. As an immuno-pathologist, his key vision is to bridge between immunologists and pathologists to better harness the advances of immunotherapy and further beyond. He is the pioneer in automating quantitative multiplex immunohistochemistry, using clinical autostainers to study and quantitate tumour immune microenvironment in clinical samples, and has published more than 100 papers in this field. His projects are part of multiple studies funded by the National Medical Research Council and sponsored by the pharmaceutical industry. Yeong was on the committee for the World Immunotherapy Council, and Society for Immunotherapy of Cancer (SITC); he helped organised the 2019 and 2023 WIC Global Symposium as well as the multiplex IF expert consensus meeting 2022. He serves as Program Chair at one of the largest AI medical Imaging conferences, CLINICCAI-MICCAI. He serves on the editorial boards of Scientific Reports, Immunoinformatics, SLAS Technology, Frontiers, and Pathogens, as well as being the Editor-in-Chief for World Scientific Annual Review of Cancer Immunology. He is a Secretary (Executive) in the Singapore Society of Oncology – Cancer Immunotherapy Consortium, a Co-lead in Education/Diagnostic for the Singhealth Duke-NUS Cell Therapy Centre as well as an Advisor (Spatial Technology) for the Cancer Discovery Hub, National Cancer Centre. In 2023, he co-founded the World Immunotherapy Council Asia to promote tumour immunology and advance cancer immunotherapy education, information and research across Asia.
In 2018, Xinru Lim joined Joe Yeong’s lab at A*STAR’s Institute of Molecular and Cell Biology (IMCB) where she oversaw the development of the infrastructure and functionalities of the new lab. As a Senior Research Officer, she manages the lab in addition to conducting research focusing on cancer immunology in clinical samples. She is interested in the advancement of cell-based immunotherapy and immune/protein biomarker discovery.

This article was made for A*STAR Research by Wildtype Media Group