title: Evaluation of HLA-DR expression and T-lymphocyte infiltration in osteosarcoma.
abstract: Although in recent years the outcome of patients with osteosarcoma has considerably been improved by combining neoadjuvant chemotherapy with radical surgery, there still remains the problem of nonresponse to chemotherapy. T-lymphocytes play a critical role in tumor immunology, and MHC molecules are of central importance in the regulation of the immune response. It is the aim of this study to investigate whether T-lymphocyte infiltration of osteosarcomas and HLA-DR expression on tumor cells and infiltrating immune cells are of predictive or diagnostic value. Expression of CD3, CD8 and HLA-II was evaluated immunohistochemically on paraffin-embedded sections of 35 patients with high-grade osteosarcoma at the time of biopsy before chemotherapy and correlated with histologic response to chemotherapy, tumor size, age, alkaline-phosphatase serum levels and duration of symptoms. Thirty-four patients with osteoblastoma (n = 7), osteoid osteoma (n = 7) or fibrous dysplasia (n = 20) served as controls. Osteosarcomas were infiltrated by CD3+ (33/35, 95%) and CD8+ T-lymphocytes (24/35, 68%), non malignant bone tumors by CD3+ in 91% (31/34) and CD8+ T-lymphocytes in 74% (25/34), respectively. T-lymphocytes were positive for HLA-DR expression in 29% (10/35) in osteosarcomas and in 11% (4/34) in non-malignant controls. Osteosarcoma cells were positive for HLA-DR in 11/35 (31%) and non-malignant tumor cells in only 9% (3/34). Therefore, HLA-DR is overexpressed in osteosarcoma (p < 0.05). HLA-DR expression on osteosarcoma cells showed a positive correlation with HLA-DR expression on lymphocytes (p < 0.001) as well as with duration of symptoms and age (p < 0.05). Response to preoperative chemotherapy, gender, tumor size and serum alkaline-phosphatase levels did not correlate with the expression of the molecules tested. Our results show that HLA-DR is overexpressed in osteosarcoma cells compared to non-malignant bone-tumors. This overexpression, however, fails to serve as a predictive marker for response to neoadjuvant chemotherapy. The same is also true for tumor-infiltrating lymphocytes expressing CD3, CD8 and HLA-DR. Increased HLA-DR expression in osteosarcoma is most likely due to the immune response against the tumor.
authors.affiliation: Department of Orthopaedics, University Hospital Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Trieb
authors.forename: T
authors.initials: T
authors.lastname: Lechleitner
authors.forename: S
authors.initials: S
authors.lastname: Lang
authors.forename: R
authors.initials: R
authors.lastname: Windhager
authors.forename: R
authors.initials: R
authors.lastname: Kotz
authors.forename: S
authors.initials: S
authors.lastname: Dirnhofer
mesh_terms: D000293:Adolescent; D000328:Adult; D000469:Alkaline Phosphatase / Q000097:blood; D014408:Biomarkers, Tumor; D001859:Bone Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D017252:CD3 Complex / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D002648:Child; D005260:Female; D005357:Fibrous Dysplasia of Bone / Q000276:immunology / Q000473:pathology; D006684:HLA-DR Antigens / Q000276:immunology*; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D018215:Osteoblastoma / Q000276:immunology / Q000473:pathology; D010017:Osteoma, Osteoid / Q000276:immunology / Q000473:pathology; D012516:Osteosarcoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D014408:Biomarkers, Tumor; D017252:CD3 Complex; D016827:CD8 Antigens; D006684:HLA-DR Antigens; D000469:Alkaline Phosphatase