Restoration of alloreactivity of melanoma by transduction with B7.1.
Melanoma cells are unusual because, unlike most epithelial tumors, constitutive expression of human leukocyte antigen (HLA) class II molecules is common. To elucidate the role of HLA class II expression in the immunopathogenesis of melanoma, the authors compared HLA class II+ melanoma cells to autologous B cells with respect to their ability to stimulate primary (naïve) histoincompatible lymphocytes and T-cell clones (antigen experienced). Using primary lymphocytes (peripheral blood lymphocytes [PBLs]), melanoma cells were nonstimulatory when compared to autologous B cells. To determine whether this was caused by defective antigen processing, the authors used alloreactive T-cell clones, which require alloantigen presentation by a histocompatible stimulator cell but not costimulation. Melanoma cells stimulated the alloreactive T-cell clones in two of three clones tested, indicating that they processed and presented alloantigen. To determine whether the failure of melanoma cells to stimulate primary lymphocytes was caused by their inability to costimulate the T cells, the authors transduced the melanoma cells with B7.1 and achieved stable expression in more than 95% of the cells. The transduced cells were highly stimulatory, eliciting a 17- to 25-fold increase in proliferation by the peripheral blood lymphocytes compared with controls. Indeed, B7-expressing melanoma cells were more stimulatory than autologous B cells, which elicited an 11- to 15-fold increase compared with controls. These data indicate that melanoma cells fail to stimulate primary lymphocytes because they do not deliver costimulatory signals. Engineering HLA class II+ melanoma cells to express high levels of B7.1 may provide a way to elicit primary T-cell responses to melanoma-associated antigens.
Brady
M S
MS
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Lee
F
F
Eckels
D D
DD
Ree
S Y
SY
Latouche
J B
JB
Lee
J S
JS
D000911:Antibodies, Monoclonal / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D002461:Cell Line, Transformed; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008545:Melanoma / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D018106:CD28 Antigens; D015704:CD4 Antigens; D000949:Histocompatibility Antigens Class II; D007519:Isoantigens