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Published on: January 3, 2013
CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer
Lu Cao1,2, Kim R Bridle1,2, Ritu Shrestha1,2
1Faculty of Medicine, The University of Queensland, Brisbane, QLD 4120, Australia.
Abstract:
Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis.
Insights
Blocking CD73 and PD-L1 may improve gallbladder cancer (GBC) treatment. This study links these immune checkpoints to cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT), offering a new therapeutic strategy for aggressive GBC.
Area of Science:
- Oncology
- Immunology
- Cancer Biology
Background:
- Gallbladder cancer (GBC) is an aggressive biliary tract cancer with poor prognosis.
- Current immune checkpoint inhibitor (ICI) therapies benefit only a subset of GBC patients.
- Understanding resistance mechanisms to ICI therapy is crucial for improving treatment efficacy.
Purpose of the Study:
- To investigate the relationship between immune checkpoints (ICs), cancer stem cells (CSCs), and epithelial-to-mesenchymal transition (EMT) in GBC.
- To explore novel therapeutic strategies targeting aggressive GBC populations.
Main Methods:
- Enrichment of CSCs using a 3D culture system.
- Establishment of a reversible EMT model in the human GBC NOZ cell line.
- Assessment of ICs CD73 and PD-L1 expression in relation to CSC and EMT phenotypes.
Main Results:
- Immune checkpoints CD73 and PD-L1 were found to be closely associated with CSC and EMT phenotypes in GBC.
- Knockdown of CD73 or PD-L1 significantly reduced the proliferative and motile capacities of GBC cells.
- These findings highlight the role of the EMT-CSC-IC axis in GBC progression and ICI resistance.
Conclusions:
- Targeting CD73 and PD-L1 presents a promising therapeutic strategy for GBC.
- Blocking CD73 and PD-L1 may be effective in treating aggressive GBC populations exhibiting CSC and EMT phenotypes.
- This approach has the potential to improve overall patient prognosis in gallbladder cancer.
