Restoration of alloreactivity of melanoma by transduction with B7.1

Melanoma cells are unusual because, unlike most epithelial tumors, constitu tive expression of human leukocyte antigen (HLA) class II molecules is comm on. To elucidate the role of HLA class II expression in the immunopathogene sis of melanoma, the authors compared HLA class II+ melanoma cells to autol ogous B cells with respect to their ability to stimulate primary (naive) hi stoincompatible lymphocytes and T-cell clones (antigen experienced). Using primary lymphocytes (peripheral blood lymphocytes [PBLs]), melanoma cells w ere nonstimulatory when compared to autologous B cells. To determine whethe r this was caused by defective antigen processing, the authors used allorea ctive T-cell clones, which require alloantigen presentation by a histocompa tible stimulator cell but not costimulation. Melanoma cells stimulated the alloreactive T-cell clones in two of three clones tested, indicating that t hey processed and presented alloantigen. To determine whether the failure o f melanoma cells to stimulate primary lymphocytes was caused by their inabi lity 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 incre ase in proliferation by the peripheral blood lymphocytes compared with cont rols. Indeed, B7-expressing melanoma cells were more stimulatory than autol ogous B cells, which elicited an 11- to 15-fold increase compared with cont rols. These data indicate that melanoma cells fail to stimulate primary lym phocytes 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.