Immune Checkpoint regulators & Bile Duct cancer

FECRI team of Professor George Kannourakis, Dr Prashanth Prithviraj, Dr Revati Sharma and Dr Aparna Jayachandran have recently published their research on bile duct cancer entitled ‘Prognostic role of Immune Checkpoint Regulators in Cholangiocarcinoma: a pilot study’ in the Journal of Clinical Medicine. Dr Prithviraj is the first co-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.

Cholangiocarcinoma (CCA) is the second most common primary liver malignancy. CCA has a dismal prognosis with very limited therapeutic options. Accordingly, novel treatment modalities that are both effective and associated with durable responses are needed for the treatment of CCA. Immunotherapy in the form of immune checkpoint inhibitors (ICIs) is anticipated to be used as an effective treatment modality for CCA. However, these ICI treatments as monotherapies may benefit only a proportion of CCA patients. The prevalence and distribution of other immune modulatory molecules in CCA remains unclear.

The present study is the first to screen the expression of nineteen immune checkpoint regulators and examine the prognostic significance of these immune checkpoint regulators in CCA patients. We report that the expression of immune modulators IDO1, NT5E and FASLG was associated with poor outcomes in CCA patients. Combining elevated expression of these immune checkpoints with PD-L1 expression functioned as robust markers that could prognosticate poor outcome in CCA patients.

Our current work is the first attempt to evaluate the association between immune checkpoint modulator expression and aggressive CCA subpopulations such as cancer stem cells (CSCs) and epithelial-to-mesenchymal (EMT), providing additional insights on the molecular events responsible for prognosis prediction. In vitro studies revealed that the expression of immune checkpoint molecules was closely associated with aggressive CCA subpopulations including CSCs and cells undergoing TGF-β and TNF-α-mediated EMT. Notably, PD-L1 and NT5E expression was closely associated with EMT, while coordinate expression of NT5E and LSGAL9 with CSC marker ALDH1A1 was associated with poor outcome in CCA patients. These findings suggest that in addition to PD-L1 there are other immune-related molecules that may serve as potential prognostic biomarkers and drug targets in CCA patient, leading to lasting and durable treatment outcomes.