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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3479-3490
Effect of Costimulation and the Microenvironment on Antigen
Presentation by Leukemic Cells
A.G.S. Buggins,
N. Lea,
J. Gäken,
D. Darling,
F. Farzaneh,
G.J. Mufti, and
W.J.R. Hirst
From the Departments of Haematological Medicine and Molecular
Medicine, King's College School of Medicine and Dentistry, London, UK.
Costimulatory signals supplied by genetically modified tumor cells
can enable T-cell recognition of tumor-associated antigens that were
previously silent 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
alloantigen primarily by lowering the level of T-cell receptor (TCR)
stimulation required 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-XL. The cytokine microenvironment in which T cells are activated is crucial in determining their differentiation and consequently the nature of the immune response generated. Many tumor
cells produce immunosuppressive cytokines that may not favor the
induction of cell-mediated immunity. In this study, the presence of
CD80 on leukemic cells increased 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 factor 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 generated by leukemic
cells may suppress the immune response required for their eradication.
Thus, strategies aimed at inducing antileukemic immunity by providing
leukemic cells with costimulatory functions must ensure the presence of
an appropriate microenvironment.
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