Abstract
Simple SummaryGallbladder cancer (GBC) is an aggressive malignancy with poor prognosis. Currently, therapeutic options are mostly limited to palliative chemotherapy. Considering the advances of immunotherapy, we assessed the expression of the programmed cell death ligand-1 (PD-L1) as the most widely used predictive marker for immunotherapy response in a large Western-world GBC cohort. Additionally, we quantified the expression of the T-cell immunoreceptor with Ig and ITIM domains TIGIT/CD155 axis as an emerging immune checkpoint. Our results indicate that PD-L1 is heterogeneously expressed in Western-world GBC and associated with distinct histomorphological tumor subtypes and increased immune cell densities. We show that a high tumoral PD-L1 expression is a significant negative prognosticator. In a subset of patients, we identified expression of TIGIT in scattered immune cells, which correlated with tumoral expression of its ligand CD155. Our results suggest a subset of GBC patients to be candidates for immunotherapy via (combined) PD-L1 and TIGIT/CD155 inhibition.Inhibition of the programmed cell death protein-1/ligand-1 (PD-1/PD-L1) axis has opened a new era in the treatment of solid cancers. However, there is no data on the expression and relevance of PD-L1 in Western gallbladder cancer (GBC). We assessed PD-L1 immunohistochemically in 131 GBC patients as Tumor Proportion Score (TPS), Immune Cell Score (IC) and Combined Positivity Score (CPS). Tumor cells expressed PD-L1 in a subset of 14.7% GBC patients at a TPS cut-off of 1%. Higher PD-L1 levels above 10% and 25% TPS were reached in 4.7% and 3.1% of GBC cases, respectively. At a 10% cut-off, TPS was associated with distinct histomorphological subtypes and correlated with poor tumor differentiation. Survival analysis revealed a TPS above 10% to be a highly significant and independent negative prognosticator in GBC. PD-L1 expression was associated with increased CD4+, CD8+ and PD-1+ immune cell densities. In 14.8% of the cases, scattered immune cells expressed T-cell immunoreceptor with Ig and ITIM domains (TIGIT), which was correlated to tumoral expression of its ligand CD155. We here show that a high PD-L1 expression confers a negative prognostic value in Western-world GBC and highlight the TIGIT/CD155 immune checkpoint as a potential new target for GBC immunotherapy.
Highlights
Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, characterized by an extremely aggressive biological behavior [1]
There is a significant subset of patients who do not benefit from this treatment, which in addition may be associated with severe adverse events [13]
The majority of GBC cases were negative for programmed death ligand-1 (PD-L1) in the tumor cell compartment with only 14.7% of all cases exhibiting a Tumor Proportion Score (TPS) of at least 1% (Table 1)
Summary
Gallbladder cancer (GBC) is the most common malignancy of the biliary tract, characterized by an extremely aggressive biological behavior [1]. Dysregulation of central immune-inhibitory and -stimulating molecules, known as immune checkpoints, seems to significantly contribute to immune evasion in numerous malignancies. Among those molecules, disruption of the programmed cell death protein-1 (PD-1)/programmed death ligand-1 (PD-L1) axis was demonstrated to be of particular relevance for tumor progression and survival [7,8]. Therapeutic blockage of the PD-1/PD-L1 checkpoint has proven significant clinical benefit in many advanced solid malignancies like melanoma and non-small cell lung cancers and opened a new era of precision cancer medicine [10,11,12]. Several scoring algorithms have been implemented with indication- and drug-specific cut-offs making predictive PD-1/PD-L1 testing an increasingly complex challenge in routine pathology [17]
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