Antitumor responses induced by transgenic expression of CD40 ligand

Because CD40 ligand (CD40L) is a co-stimulator molecule for multiple components of the immune response, we wanted to determine whether transgenic expression of the molecule would increase immune responses against a weakly immunogenic murine tumor, neuro-2a, Tumor cells were transduced with a retroviral construct-containing the CD40L gene and co-injected with variable numbers of non-CD40L transduced cells into syngeneic mice, Mice injected with cells that expressed CD40L had a significant reduction in average tumor size as compared to controls (p < 0.0001), In addition, survival of the neuro-2a/CD40L mice was 48 days versus 34 days for the neuro-2a/neo controls (p < 0.02), Expression of CD40L by less than 1.5 % of neuro-2a cells was sufficient for significant antitumor effects (p < 0.001), These antitumor effects protected mice from subsequent challenge with parental neuro-2a cells, The protective effects of CD40L were associated with systemic immunomodulation. In vivo depletion of CD8(+) cells abrogated the CD40L-mediated antitumor effects, Analysis of spleens from CD40L-protected animals showed increased numbers of CD4(+) and CD8(+) cells, the majority of which co-expressed the activation marker CD25, In addition, an increased number of antigen-presenting cells (APCs) expressed the co-stimulatory molecule CD86, These experiments illustrate that transducing even a small percentage of tumor cells with CD40 ligand can create a long-lasting systemic immune response capable of impeding growth of unmodified neuroblastoma cells.