Differential effect of the immunomodulator AS101 on B7-1 and B7-2 costimulatory molecules: Role in the antitumoral effects of AS101

The CD28 receptor on T cells with its ligand B7, representing the best characterized example of costimulation, has recently been demonstrated to interact with two different ligands: B7-1 and B7-2. AS101 (ammonium trichloro[dioxoethylene-0,0']tellurate), a synthetic immunomodulator with minimal toxicity, was previously shown to stimulate both mouse and human cells to proliferate and secrete a variety of cytokines. We recently found that treatment of advanced cancer patients or tumor-bearing mice with AS101 results in a clear predominance of Th1 responses with a concomitant decrease in Th2 response. Our present study demonstrates that AS101 differentially affects B7-1 and B7-2 molecule expression on mouse macrophages: it up- regulates B7-1 expression in a dose-dependent manner without affecting B7-2 expression, which leads to a profound macrophage costimulatory activity of purified T cells with soluble anti-CD3. Our results also demonstrate the differential inhibitory effect of IL-10 on T cell activation in the presence of AS101-stimulated accessory cells (AC). We show that when stimulated with AS101, AC-dependent T cell activation was more resistant to inhibition by IL- 10 compared with AC stimulated by LPS. This was due to the partial resistance of AS101-stimulated macrophages to the down-regulation of B7-1 expression by IL-10. In vivo studies with AS101-treated tumor-bearing mice revealed that the predominance in Th1 responses-marked by an increase in IFN-γ and a decrease in IL-4-may be associated in part with the ability of AS101 to up- regulate B7-1 expression, which is also related to its antitumoral effects. These results suggest that AS101 may be clinically effective in conditions involving dysfunctional cytokine production.