In brief

Targeting specific biomarkers like CD38 could make liver cancer therapy more effective.

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Striking with precision at liver cancer

9 Apr 2021

A new biomarker in liver tumor may help doctors predict how patients respond to immunotherapy.

For decades, our arsenal of cancer treatments was fairly predictable—oncologists could turn to surgery, radiotherapy or chemotherapy, which are cytotoxic drugs linked to severe side effects.

But the ground is shifting thanks to the emergence of immunotherapy, a powerful cancer treatment modality that mobilizes a patient’s immune system to detect and destroy tumor cells. Unlike chemotherapy, which only targets the tumor, immunotherapy can also be used to target the tumor microenvironment in addition to the tumor itself.

Despite their potential, immunotherapies are not a ‘one-size-fits-all’ approach to treating cancer; only a small subset of patients respond to and benefit from immunotherapies such as PD-1/PD-L1 inhibitors, and doctors don’t always know why.

According to experts, there is a way to manage this uncertainty and map the best therapeutic path forward for individual patients. This involves categorizing patients based on the presence of biomarkers—signature molecular characteristics present in their tumors.

“For personalized and precision medicine, stratifying patients to manage them uniquely is key,” explained study co-corresponding author Joe Yeong, a Group Leader at A*STAR’s Institute of Molecular and Cell Biology (IMCB).

Together with an interdisciplinary team of immunologists, pathologists and oncologists, Yeong embarked on a search for predictive biomarkers in hepatocellular carcinoma (HCC), the third most common cause of cancer-related mortality in the Asia-Pacific region.

Starting with HCC tissue samples from 49 Asian patients, the team used a technology called multiplex immunohistochemistry, which allowed them to visualize multiple proteins of interest simultaneously.

Their biomarker of interest was CD38, an immune protein that Yeong’s team first reported in 2019 to be expressed on the surface of macrophages—immune cells that infiltrate tumors and upon activation by immunotherapies, can initiate their destruction.

In this latest study, Yeong and colleagues confirmed that CD38 was expressed by macrophages and myeloid immune cells in the tumor microenvironment of HCC patients who were treated with PD- 1/PD-L1 inhibitors. Further analysis showed that CD38 gene expression is a predictive marker in HCC, and that total CD38 cell proportion could predict response to immunotherapy in HCC.

“By using CD38 as a biomarker, we can identify patients who can potentially benefit from immunotherapy for HCC,” Yeong said. “More importantly, patients who do not express a certain level of CD38 should be treated with other treatment such as radiotherapy, targeted therapy or chemotherapy first, before thinking about immunotherapy.”

Follow-up studies are aimed at validating these findings in larger, multinational patient cohorts, including among Caucasian populations. Yeong is also working with industry partners to translate their findings for use in clinical settings.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Molecular and Cell Biology (IMCB) and the Singapore Immunology Network (SigN).

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Ng, H.H.M., Lee, R.Y., Goh, S., Tay, I.S.Y., Lim, X., et al. Immunohistochemical scoring of CD38 in the tumor microenvironment predicts responsiveness to anti-PD-1/PD-L1 immunotherapy in hepatocellular carcinoma. Journal for ImmunoTherapy of Cancer 8:e000987 (2020) | article

About the Researcher

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.

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