The immune microenvironment and expression of members of the B7 family of immune checkpoints are prognostic in osteosarcoma

Abstract

Osteosarcoma is a malignant neoplasm defined by the presence of pleomorphic spindle shaped cells capable of forming osteoid. There have been minimal improvements in survival outcomes over the past four decades, particularly in patients with refractory or relapsed disease, or those with macroscopic metastatic disease at presentation. Immune evasion, which occurs when tumor cells escape detection by the immune system, represents a novel therapeutic target. Overexpression of the B7 family of immune checkpoints, specifically PD-L1 and HHLA2, can lead to immune evasion. We hypothesized that osteosarcoma, a genetically complex cancer, would have high levels of immune infiltration leading to expression of PD-L1 and HHLA2. We found that up to 85% of osteosarcoma tumors, at the time of biopsy, definitive surgery, and in metastatic disease samples, displayed lymphocyte infiltration.. Tumor infiltration by a subset of immune cells: T cells, dendritic cells, and natural killer cells, was associated with tumor expression of PD-L1. PD-L1 was heterogeneously expressed in a small area of twenty five percent of tumors. HHLA2 was homogenously expressed in up to 90% of osteosarcoma lung metastases and 87% of primary tumors. HHLA2 expression appeared to be associated with metastasis, with lung metastases expressing HHLA2 more frequently than primary tumors with no known metastases. Expression of HHLA2, PD-L1, and tumor infiltration by antigen presenting dendritic cells were all associated with significantly worse survival outcomes. Our results suggest a role for the immune system in osteosarcoma and that PD-Ll and HHLA2 are both promising therapeutic targets in osteosarcoma.