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HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival.

ABSTRACT: Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n?=?62). The association of HHLA2 with the presence of tumor infiltrating lymphocytes (TILs) and five-year-event-free-survival were examined. HHLA2 was expressed in 68% of osteosarcoma tumors. HHLA2 was expressed in almost all metastatic disease specimens and was more prevalent than in primary specimens without known metastases (93% vs 53%, p?=?0.02). TILs were present in 75% of all osteosarcoma specimens. Patients whose tumors were ?25% or ?50% HHLA2 positive had significantly worse five-year event-free-survival (33% vs 64%, p?=?0.03 and 14% vs 59%, p?=?0.02). Overall, we have shown that HHLA2 is expressed in the majority of osteosarcoma tumors and its expression is associated with metastatic disease and poorer survival. Along with previously reported findings that HHLA2 is a T cell co-inhibitor, these results suggest that HHLA2 may be a novel immunosuppressive mechanism within the osteosarcoma tumor microenvironment.

SUBMITTER: Koirala P

PROVIDER: S-EPMC4987662 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival.

Koirala Pratistha P Roth Michael E ME Gill Jonathan J Chinai Jordan M JM Ewart Michelle R MR Piperdi Sajida S Geller David S DS Hoang Bang H BH Fatakhova Yekaterina V YV Ghorpade Maya M Zang Xingxing X Gorlick Richard R

Scientific reports 20160817

Over the past four decades there have been minimal improvements in outcomes for patients with osteosarcoma. New targets and novel therapies are needed to improve outcomes for these patients. We sought to evaluate the prevalence and clinical significance of the newest immune checkpoint, HHLA2, in osteosarcoma. HHLA2 protein expression was evaluated in primary tumor specimens and metastatic disease using an osteosarcoma tumor microarray (TMA) (n = 62). The association of HHLA2 with the presence of ...[more]

PMID: 27531281

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Project description:PurposeHHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.Experimental designAn immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.ResultsHHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.ConclusionsWide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

Dataset Information

HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival.

Publications

HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival.

Similar Datasets

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