CD73 and PD-L1 as Potential Therapeutic Targets in Gallbladder Cancer.

Lu Cao,Kim R Bridle,Aparna Jayachandran,Ritu Shrestha,Prashanth Prithviraj,Darrell H G Crawford

doi:10.3390/ijms23031565

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.

Highlights

Gallbladder cancer (GBC) is a rare but highly lethal cancer of the biliary tract system with estimated 5-year overall survival rates of 19% for all stages jointly analyzed and 2%in a metastatic setting [1]
As increased migratory ability is an important feature associated with cancer metasAs increased migratory ability is an important feature associated with cancer metastasis, we further examined whether the repression of CD73 and programmed cell death ligand-1 (PD-L1) reduces motile betasis, we further examined whether the repression of CD73 and PD-L1 reduces motile haviour associated with GBC cells
With the immune checkpoint inhibitors (ICIs) opening a new arena of targeted therapy in a number of solid neoplasms including liver cancers, novel ICI-based immunotherapies may yield promising responses in GBC patients

Summary

Introduction

Gallbladder cancer (GBC) is a rare but highly lethal cancer of the biliary tract system with estimated 5-year overall survival rates of 19% for all stages jointly analyzed and 2%in a metastatic setting [1]. According to GLOBCAN, whilst 1.2% new cases of GBC are diagnosed annually, GBC accounts for 1.7% of all cancer deaths worldwide [2,3,4]. The extremely poor prognosis of GBC is ascribed to the prolonged asymptomatic early stage with atypical clinical symptoms, late diagnosis with unresectable or metastatic disease, and suboptimal treatment modalities [5]. Standard first-line treatment options including chemotherapy and radiotherapy confer modest survival benefit for locally advanced and metastatic stages of GBC [6]. Currently no immune checkpoint inhibitors (ICIs) or targeted therapies against actionable mutations have been approved for treatment of GBCs. there is a pressing need for exploring novel and better treatment strategies to improve survival in GBC patients

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