title: 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.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Pratistha
authors.initials: P
authors.lastname: Koirala
authors.affiliation: Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Roth
authors.affiliation: Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Gill
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Jordan M
authors.initials: JM
authors.lastname: Chinai
authors.affiliation: Department of Pathology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Ewart
authors.affiliation: Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Sajida
authors.initials: S
authors.lastname: Piperdi
authors.affiliation: Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.|Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Geller
authors.affiliation: Department of Orthopedic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Bang H
authors.initials: BH
authors.lastname: Hoang
authors.affiliation: Sophie Davis School of Biomedical Education, Manhattan NY, USA.
authors.forename: Yekaterina V
authors.initials: YV
authors.lastname: Fatakhova
authors.affiliation: Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Ghorpade
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA.|Division of Pediatric Hematology, Oncology, Marrow &Blood Cell Transplantation, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Gorlick
mesh_terms: D000293:Adolescent; D000328:Adult; D060890:B7-H1 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000276:immunology; D001859:Bone Neoplasms / Q000276:immunology* / Q000473:pathology; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008297:Male; D012516:Osteosarcoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D011379:Prognosis; D040081:Protein Array Analysis; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C400341:HHLA2 protein, human; D007136:Immunoglobulins