HHLA2 in intrahepatic cholangiocarcinoma: an immune checkpoint with prognostic significance and wider expression compared with PD-L1

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.Electronic supplementary materialThe online version of this article (10.1186/s40425-019-0554-8) contains supplementary material, which is available to authorized users.

Predictive biomarkers and mechanisms underlying resistance to PD1/PD-L1 blockade cancer immunotherapy

“…Low PD-L1 expression is also a major cause of poor PD-1 blocking; accordingly, co-inhibitory receptors are a promising area of research. The newly discovered T cell B7 family immune checkpoint, HHLA2, is a cotherapeutic target for PD-L1, improving the number and activity of T cells in the tumor microenvironment [165]. Another co-inhibitory receptor, KLRG1, expressed on late-differentiated effector cells and CD8 + T and NK cells, is up-regulated in treated tumor samples, resulting in drug resistance; blocking both KLRG1 and PD-1 can improve outcomes [166].…”

Potential Therapeutic Targets of B7 Family in Colorectal Cancer

“…In contrast to that in normal tissues, the protein expression of HHLA2 is widely observed in most of tumor specimens from the colon, breast, lung, thyroid, pancreas, ovary, liver, bladder, prostate, kidney, and esophagus, as well as in melanoma specimens (59). Several studies showed that overexpression of HHLA2 was significantly correlated with poor survival and clinical outcomes in patients with bladder urothelial carcinoma (60), clear cell renal cell carcinoma (61), osteosarcoma (62), and intrahepatic cholangiocarcinoma (63). However, high HHLA2 expression predicts better survival for patients with pancreatic cancer (64) and unresectable advanced or recurrent gastric cancer (65).…”

Phenotypical and potential functional characteristics of different immune cells expressing CD28H/B7-H5 and their relationship with cancer prognosis

“…In a study on ICC , B7‐H5 was identified as an independent prognostic indicator for OS. B7‐H5 was used as an inhibitory checkpoint and it was found that B7‐H5 expression was more frequent in ICC than PD‐L1 (49·0 versus 28·1%).…”