Our team’s research into liver cancer has received endorsement by two recent publications.
A paper entitled, ‘Immune checkpoint molecules are regulated by transforming growth factor (TGF)-β1-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma’ has recently been published in the published in the International Journal of Medical Sciences. Dr Aparna Jayachandran is the senior and corresponding author on this publication. This work has been conducted in close collaboration with liver cancer researchers at the Gallipoli Medical Research Institute and the University of Queensland, Brisbane.
Thsi work focuses onHepatocellular carcinoma (HCC), a common primary liver malignancy accounting for approximately 80-90% of all liver cancers. HCC is frequently diagnosed in cirrhotic patients with higher risk in patients with underlying liver disease resulting mainly from hepatitis B or C virus infection. The global burden of HCC is increasing rapidly but treatment options are still limited. Cancer immunotherapy based on immune checkpoint inhibitor drugs have transformed treatment in several cancers including HCC. Checkpoint inhibitor drugs work by blocking the activity of T-cells and other immune system components, thus boosting these cells’ antitumor activity. Despite the promising clinical effects of checkpoint inhibitor drugs in patients with HCC, the overall response rates in patients have been low. There is an urgent need for biomarkers that can predict immunotherapy response in HCC patients and to better understand how immune checkpoints are regulated in these cancer cells.
The current study provides valuable insights into the molecular mechanisms regulating immune checkpoint expression in HCC and identified biomarkers associated with poor prognosis in HCC patients. Our current work is the first attempt to utilize a reversible cell culture model to demonstrate the close association between immune checkpoints, cytokine transforming growth factor (TGF)-β1 and the aggressive cellular process of epithelial-to-mesenchymal transition (EMT). Importantly, we also observed that HCC patients with coordinate expression of TGF-β1 and immune checkpoint molecules PD-L1 or B7-H3 had poor overall survival. Moreover, this study suggests that EMT markers may be useful biomarkers to predict patient response in ICI immunotherapy.
Dr Aparna Jayachandran has also published research with fellow FECRI scientist Dr Prashanth Prithviraj on liver cancer entitled ‘Combined inhibition of TGF-β1-induced EMT and PD-L1 silencing re-sensitizes hepatocellular carcinoma to Sorafenib treatment’ in the Journal of Clinical Medicine. Dr Prithviraj is the second author and Dr Jayachandran is the senior and corresponding author on this publication. This work has been conducted in close collaboration with liver cancer researchers at the Gallipoli Medical Research Institute and the University of Queensland, Brisbane.
This work also focused on Hepatocellular carcinoma (HCC) increased therapy resistance and circumventing resistance to oral multi-tyrosine kinase inhibitor, Sorafenib. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways contributing to Sorafenib resistance is an area of pressing need.
The current study focuses on epithelial-to-mesenchymal transition (EMT), a cellular process which confers HCC tumour cells with the ability to evade the immune system and develop resistance to Sorafenib treatment. The present study is the first to examine the association between cytokine transforming growth factor (TGF)-β1-induced EMT, aberrant immune checkpoint expression and Sorafenib resistance in HCC. Notably, this is the first study to report that combined inhibition of TGF-β1-induced EMT and immune checkpoint PD-L1, can re-sensitize HCC cells to Sorafenib treatment. We conclude that the combination of TGF-β receptor kinase inhibitor and immune checkpoint inhibitor can synergistically impeded EMT and potentially improve the sensitivity of HCC cells to Sorafenib. These findings provide a valuable strategy to potentially improve the clinical efficacy of Sorafenib in HCC patients by utilizing combinatorial treatment approach with PD-L1 blocker and TGF-β inhibitor.