Cancer cells are strikingly different from healthy ones, leaving tell-tale signs that can be detected by immune cells. So how do these malignant tissues mask their true identities to avoid capture by the immune system? According to a study published in Cell, some liver cancer cells have an unusual way of surviving: By pretending to be growing fetal cells.
“The fetal immune system and fetoplacental-maternal interface are largely immunologically tolerant, allowing their co-existence within the mother until birth,” explained Ramanuj DasGupta, a Senior Group Leader at A*STAR’s Genome Institute of Singapore (GIS). “It has long been suggested that cancers may have similar mechanisms to avoid rejection by the body’s own immune system.”
Together with Pierce Chow of the National Cancer Centre Singapore; Jerry Chan of KK Women’s and Children’s Hospital; Florent Ginhoux of A*STAR’s Singapore Immunology Network (SIgN); and the study’s first author, Ankur Sharma, a postdoctoral fellow in his lab, DasGupta focused on a form of liver cancer called hepatocellular carcinoma (HCC), the second most common cause of cancer deaths globally.
The team analyzed gene expression profiles of around 200,000 single human liver cells isolated at different stages of both fetal and tumor development. The creation of this single-cell atlas was the key driver in discovering new aspects of tumor biology, particularly among rarer populations of HCC tumor cells, said DasGupta.
Interestingly, the researchers found cells typically associated with the development of the fetal liver within HCC tumors. These cells, which include endothelial cells and macrophages, activate specific signaling pathways allowing tumors to thrive under the prying eyes of circulating immune cells. The tumor cells do so by altering their microenvironment in a way that promotes immune exhaustion or exclusion, or both. As a consequence, the cytotoxic immune cells can’t infiltrate the tumor, or even if they do, are not activated to recognize and kill the tumor cells.
In particular, gene regulatory analysis showed that VEGF signaling between the HCC cells and endothelial cells can impart ‘fetal-like’ characteristics to the latter, which in turn activate the Notch-Delta pathway in blood monocytes and differentiate them into immune-suppressive macrophages.
“This study not only provides fundamental insights into the developmental origins of cancer and the specific processes that drive tumorigenesis, but may also usher in the development of new therapeutic strategies to re-activate the immune system in the fight against cancer,” said DasGupta. With over 80 percent of HCC patients hailing from Asian countries, these developments could significantly impact the region.
Moving forward, the team is exploring the utility of their newly-discovered biomarkers as potential therapeutic targets, particularly when used in combination with existing immunotherapies. They are also investigating whether other solid tumors employ similar immune evasion tactics and how epigenetic factors influence these processes.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS) and Singapore Immunology Network (SIgN).
