Potentiation of lymphocyte responses by monoclonal antibodies to the ganglioside GD3.

Previous studies have shown that the ganglioside GD3 is expressed in high concentrations on melanoma cells and that monoclonal antibodies (MAbs) against GD3 may induce partial remissions in tumor growth in patients with melanoma. The present studies indicated that incubation of interleukin 2 (IL2) dependent murine natural killer cells with several MAbs against the ganglioside GD3 potentiated the proliferative response to IL2. There was no effect on cell division in the absence of added IL2. Similarly the mitogenic response of human blood lymphocytes to phytohemagglutinin (PHA) or the T3 antigen was enhanced by coculture with these MAbs. This was noted when the MAbs to GD3 were added either before or up to 48 h after addition of PHA or MAb to T3. Kinetic analysis revealed that the potentiation of the PHA induced mitogenic response followed the expected response to PHA suggesting that the MAbs amplified normal activation pathways. These effects were also seen wih MAb to GD3 and the T10 structure on T-cells but not with MAbs to the transferrin receptor or isotype MAb controls. Studies on T-cell subsets suggested that the enhanced PHA responses were confined mainly to the T8 subset and responses of the T4 subset were not enhanced. Flow cytometric analysis revealed low levels of GD3 expression on blood lymphocytes which increased during culture with PHA. IL2 receptor (Tac epitope) expression did not show close correlation with the enhanced lymphocyte responses and the mechanism of the potentiation remains uncertain. These studies raise questions concerning the role of gangliosides in T-cell activation and whether these in vitro effects of MAbs to GD3 may account in part for their antitumor effects in patients with melanoma.