Abstract
BackgroundIntrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Immunotherapies targeting PD-1/PD-L1 pathway represent a promising treatment for ICC. However, PD-L1 expression and microsatellite instability are not common in ICC. This study aimed to investigate whether HHLA2, a newly identified B7 family immune checkpoint for T cells, could be a therapeutic target next to PD-L1 in ICC.MethodsExpression levels of PD-L1 and HHLA2 as well as infiltrations of CD3+, CD8+, CD4 + Foxp3+, CD68+, CD163+ and CD20+ cells were evaluated by immunohistochemistry in 153 resected ICC samples. Comprehensive comparisons were made between PD-L1 and HHLA2 in terms of the expression rates, clinicopathological features and infiltrations of different immune cells. The expression level and prognostic significance of HHLA2 were further validated in an independent cohort.ResultsExpression of HHLA2 is more frequent than PD-L1 in ICC (49.0% vs 28.1%). Co-expression of both immune checkpoints was infrequent (13.1%) and 50% PD-L1 negative cases were with elevated HHLA2. HHLA2 overexpression was associated with sparser CD3+ tumor infiltrating lymphocytes (TILs), CD8+ TILs and a higher CD4 + Foxp3+/CD8+ TIL ratio, whereas PD-L1 expression was associated with prominent T cells and CD163+ tumor associated macrophages infiltrations. PD-L1 failed to stratify overall survival (OS) but HHLA2 was identified as an independent prognostic indicator for OS in two independent cohorts.ConclusionsCompared with PD-L1, HHLA2 is more prevalent and possesses more explicit prognostic significance, which confer the rationale for HHLA2 as a potential immunotherapeutic target next to PD-L1 for ICC patients.
Highlights
Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options
In this study, we observed that HHLA2, a newly identified B7 family member, was more prevalent than program cell death (PD)-L1 in ICC and HHLA2 overexpression was common in PD-L1 negative ICC
HHLA2 was identified as an independent prognostic indicator for overall survival (OS) in two independent cohorts whereas PD-L1 showed no significant prognostic value
Summary
Intrahepatic cholangiocarcinoma (ICC) is a highly mortal malignancy with limited therapeutic options. Surgical resection offers the only chance to cure, but most ICC patients are diagnosed at advanced clinical stages when only palliative treatments can be performed [1]. Some of these palliative treatments are proved to be effective, but their prolongations of survival are still unsatisfactory [1, 3, 4]. Immunotherapies that normalize immune responses in the tumor microenvironment (TME), through targeting the program cell death (PD) pathway, have been proved to achieve high objective response rates in several refractory malignancies [5,6,7]. Anti-PD therapy has been approved by FDA with more than 10 cancer indications, and PD-L1 expression level in tumor samples is an important biomarker to predict treatment responses of anti-PD therapy [8]
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