Oncofetal ecosystems linked to recurrence and immunotherapy response in liver cancer

A team of clinician-scientists and researchers from the National Cancer Centre Singapore (NCCS), Agency for Science, Technology and Research (A*STAR), the Harry Perkins Institute of Medical Research and global research partners, has found a causal link between the presence of oncofetal ecosystems (re-emergence of fetal programme/features driven by the tumor) in the primary liver cancer hepatocellular carcinoma (HCC) and cancer recurrence and response to immunotherapy. These game-changing findings, which pave the way for the use of oncofetal ecosystems as biomarkers to treat HCC, were recently published in Nature Cancer on 2 January 2024.

Liver cancer is the sixth most common cancer in the world and fourth most common cause of cancer deaths globally. In Singapore, it is the third most common cause of cancer deaths in males and fifth most common cause in females. HCC is usually diagnosed at a late stage, when prognosis is poor, highlighting a great clinical need to improve the understanding of HCC to better manage the disease.

An earlier breakthrough study, from the same research team, found that HCC cells adopt a foetal-like environment to escape immune surveillance and grow more aggressively. This provided novel insights into the processes that drive HCC development.

In their latest work published in Nature Cancer this year, the team built on their previous discovery and focused on understanding how the changes in the oncofoetal ecosystem, known as oncofoetal reprogramming, impacts HCC. Oncofoetal reprogramming causes the cancer cell environment in the liver to mimic certain aspects of cells in foetal development, leading to the suppression of the body's immune system. The team compiled a single-cell atlas of 251,761 cells from over 80 donors with liver cancer and used advanced techniques, such as single-cell RNA sequencing and single-cell spatial transcriptomics, to analyse them. The team identified a cell called POSTN+ cancer-associated fibroblast to be central in this process.

Further analysis revealed that oncofoetal reprogramming is implicated in EMT (epithelial to mesenchymal transition-;which typically makes cancer more aggressive) and tumour cell proliferation, ultimately playing a role in early recurrence and response to immunotherapy.

Oncofetal cells are very adaptable and behave like embryonic cells. They originate within the tissue surrounding tumors and provide a 'fertile soil' for 'malignant seeds'. This is the reason that even after a tumour has been surgically removed, these cells remain and can lead to cancer recurrence. By analysing the microenvironment, which surrounds and nourishes the tumour, we found some patients have high levels of foetal-like cells. Their presence predicts the likelihood of recurrence."

Ankur Sharma, study co-senior author, Professor, Lab Head of the Onco-Fetal Ecosystem Laboratory at the Harry Perkins Institute of Medical Research in Perth, Western Australia

"This translational discovery based on basic research mapping the tumour microenvironment, not only provides us with a novel biomarker but, more importantly, offers a tangible solution to better treat HCC – a ray of hope for patients and a new direction for oncology," said study co-senior Associate Professor Florent Ginhoux, Senior Principal Investigator, A*STAR's Singapore Immunology Network (SIgN).

"We can now link the discovery of foetal-like reprogramming of the tumour ecosystem with a clinical outcome in HCC patients. This is very significant, as it opens promising opportunities to group early-stage HCC patients that have higher likelihood of early recurrence and improve their care management. It also presents the possibility of therapeutically targeting the cell-based signature in the tumour microenvironment with combined immunotherapy," said study co-senior author Professor Pierce Chow, Senior Consultant Surgeon, Singapore General Hospital and NCCS and Professor, Duke-NUS Medical School.

Additionally, the team plans to investigate whether foetal POSTN+ cancer-associated fibroblasts are also presented in other cancers. Further clinical application of this study would be to develop a biomarker that shows response to combined immunotherapy.

This research is supported by the Singapore Ministry of Health's National Medical Research Council under its Open Fund-Large Collaborative Grant (MOH-001067), Translational Research Investigator Award (TCR/015-NCC/2016), and by the Biomedical Research Council (BMRC) use-inspired basic research (UIBR) award and the National Research Foundation Singapore under its Singapore National Research Foundation Senior Investigatorship (NRF2016NRF-NRFI001-02). It is also supported by the National Health and Medical Research Council (NHMRC) Ideas Grant [2021/GNT2010795], Medical Research Future Fund (MRFF) Early to Mid-Career Researchers (EMCR) grant [2022/MRF2016215].