B7-H3 Identified as Potential Target for Treatment of Giant Cell Lesions of Bone
Key findings
- A T-cell immune response was identified in all giant cell lesions of bone examined
- Low CD8+ T-cell infiltration was associated with aggressive tumors
- Low expression of HLA antigens in combination with low CD8+ T-cell infiltration was associated with highest risk of tumor aggressiveness
- High B7-H3 expression combined with high levels of CD8+ T-cell infiltration was associated with higher tumor aggressiveness
- Drugs that target B7-H3 may be an effective treatment against giant cell lesions of bone
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For treatment of giant cell lesions of bone, the drug denosumab has been shown to be an effective adjunct to surgery. However, the lesions recur once the drug is stopped, and the long-term effect of denosumab is poorly understood. Therefore, scientists are continuing to study the pathophysiology of giant cell lesions in hopes of identifying improved drug targets.
A major focus of cancer research today is the study mechanisms that allow tumors to avoid attack by immune cells. Despite having functional human leukocyte antigens (HLA) class I, some tumors express immune inhibitory proteins that allow them to escape the immune response and invade surrounding tissues. One such protein, B7-H3, is known to have immunosuppressive properties in several cancer types. B7-H3 is an immune system regulatory “check point,” similar to programmed cell death protein 1, the target of pembrolizumab, nivolumab and other drugs that have been quite successful against multiple types of cancer.
Researchers at Massachusetts General Hospital have found that locally aggressive giant cell lesions have lower HLA class I expression, lower CD8+ lymphocyte infiltration, and higher expression of B7-H3, compared with nonaggressive lesions. Lead investigator Joseph H. Schwab, MD, chief of the Orthopaedic Spine Center, and colleagues report their findings in Clinical Orthopaedics and Related Research.
The team reviewed the records of 93 patients (56% female, average age 28) who were surgically treated for giant cell lesions between January 1993 and June 2008 and had at least six months of follow-up. The series included 45 patients with maxillofacial lesions (38 aggressive and seven nonaggressive) and 48 patients with axial or appendicular lesions (30 aggressive and 18 nonaggressive).
The researchers constructed a microarray containing 288 tissue cores from the patients. They immunohistochemically stained the microarray with monoclonal antibodies specific for HLA class I antigens and B7-H3 antigens, then analyzed for tumor-infiltrating lymphocytes.
Lymphocyte infiltrates were identified in all giant cell lesions, meaning that the immune system was recognizing and responding to them. CD4+ and CD8+ lymphocytes were found in 90% and 84% of tumors, respectively. The median number of CD8+ lymphocytes was lower in aggressive tumors (4.8) than in nonaggressive tumors (15.8). This suggests, the researchers note, that the immune system plays an active role in determining disease status.
Their next step was to investigate the prognostic value of HLA class I antigen expression and CD8+ lymphocyte infiltration. They found that low expression of HLA antigens, plus low CD8+ infiltration, was associated with a significantly higher risk of tumor aggressiveness, compared with high HLA antigen expression and high CD8+ levels.
Finally, the researchers determined that the combination of high B7-H3 expression and low CD8+ lymphocyte infiltration was associated with significantly greater tumor invasiveness. This suggests, they say, that B7-H3 has an inhibitory immune function in giant cell lesions.
The authors conclude that immunotherapy that targets B7-H3 may hold promise for treating giant cell lesions of bone.
This research won Dr. Schwab and his colleagues the Richard A. Brand Award for Outstanding Orthopaedic Research, given annually by The Association of Bone and Joint Surgeons and the Orthopaedic Research Society.
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