Effect of costimulation and the microenvironment on antigen presentation by leukemic cells

Costimulatory signals supplied by genetically modified tumor cells can enab le T-cell recognition of tumor-associated antigens that were previously sil ent when presented by unmodified tumor cells. Although the mechanism of the CD80/CD28 costimulation has been studied extensively in the normal T-cell/ antigen-presenting cell (APC) interactions, it is unclear how expression of CD80 by tumor cells mediates its effect. We demonstrate here that optimal CD80 expression on a leukemic cell enhances T-cell recognition of alloantig en primarily by lowering the level of T-cell receptor (TCR) stimulation req uired for activation. CD80 expression by leukemic cells leads to increased survival of activated T cells by inducing upregulation of the antiapoptotic protein BCL-2, but not BCL-X-L. The cytokine microenvironment in which T c ells are activated is crucial in determining their differentiation and cons equently the nature of the immune response generated. Many tumor cells prod uce immunosuppressive cytokines that may not favor the induction of cell-me diated immunity. In this study, the presence of CD80 on leukemic cells incr eased T-cell activation in vitro, but this did not result in the production of Th1 cytokines. We show that this is due to a leukemia-derived soluble f actor that inhibits the production of Th1 cytokines. Optimal expression of a costimulatory molecule, therefore, enhances the ability of leukemic cells to present antigen by amplifying TCR signals, but the microenvironment gen erated by leukemic cells may suppress the immune response required for thei r eradication. Thus, strategies aimed at inducing antileukemic immunity by providing leukemic cells with costimulatory functions must ensure the prese nce of an appropriate microenvironment. (C) 1999 by The American Society of Hematology.