CD40 ligand as a co-stimulator molecule for the generation of an antitumor response

Leukemic cells may escape immune surveillance by their lack of co-stimulatory molecules. CD40 ligand (gp39) is a cell surface molecule expressed by T cells and antigen presenting cells that acts as a co-stimulator molecule for T and B cell responses. This activity led us to investigate whether transgenic expression of the CD40 ligand (CD40L) can induce systemic anti-leukemic activity against the otherwise non-immunogenic A20 B cell leukemic cell line. We found that in the presence of transgenic CD40L, A20 leukemia cells upregulate expression of B7.1 (CD28), Class and II MHC, effects that favor successful tumor-antigen presentation. There was also upregulation of FAS and enhanced apoptosis allowig for uptake and presentation of tumor-antigens by professional antigen-presenting cells. We then used an A20 tumor immunisation model to show that expression of CD40L at one tumor site significantly delays growth of pre-existing tumor (p<0.05) in comparison to the control. Because CD40L also upregulates T cell function directly, we analyzed the effects on tumor growth and survival after combining CD40L with the T cell growh factor IL2. In the same model, the response to pre-existing distal tumor was significantly greater in mice treated with a combination of these co-stimulatory molecules (CD40L+1L2) than with either agent alone (p<0.005 in comparison to IL2 and CD40L alone). The CD40L and IL2-mediated anti-tumor effect was dependent on intact CD4+ and CD8+ T lymphocyte and NK cell systems, as depletion of either of these lymphoid subsets by antibody injection partially abrogated the anti-leukemia response. The enhanced response occured even though the cytokine and the co-stimulatory surface molecules were expressed on accessory cells separate from the tumor cells, simplifying the logistic demands of future clinical protocols that may adopt this dualagent strategy.