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

Pratistha Koirala,Jordan M Chinai,Yekaterina V Fatakhova,Richard Gorlick,Xingxing Zang,Jonathan Gill,Bang H Hoang,Sajida Piperdi,Maya Ghorpade,Michelle R Ewart,Michael E Roth,David S Geller

doi:10.1038/srep31154

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.

Highlights

Median age years (SD) Huvos Response Good Poor No clinical data Metastasis Present Absent No clinical data Site Long Bone Other No clinical data
Fifty-four samples from the tumor microarray (TMA) had associated clinical data, of which 14 (26%) were specimens obtained at the time of initial biopsy, 28 (52%) were specimens obtained at the time of definitive surgery, and 13 (22%) were obtained from metastatic tumors (Table 1)
An additional two specimens obtained at the time of initial biopsy, 17 specimens obtained at the time of definitive surgery, and five metastatic tumor specimens were available for analysis of HHLA2 and TILs, did not have either associated clinical outcome or demographic data

Summary

Introduction

Median age years (SD) Huvos Response Good Poor No clinical data Metastasis Present Absent No clinical data Site Long Bone Other No clinical data. HHLA2 is the most recently identified member of the B7 family[13,17,18,19]. Unlike other members of the B7 family, HHLA2 is not expressed in mice or rats[13,18]. HHLA2 is expressed on peripheral blood monocytes and can be induced on B cells[13,19]. HHLA2 does not bind to any other members of the B7 family or their receptor CD28 family, rather it functions via binding to TMIDG2 and a potential second unknown receptor[13,19,20,21,22]. HHLA2 expression was associated with the presence of lymph node metastasis and higher stage disease in patients with TNBC. We assess the expression patterns of HHLA2 in osteosarcoma in the context of the immune microenvironment

Methods

Results

Conclusion