ANTITUMOR RESPONSES INDUCED BY TRANSGENIC EXPRESSION OF CD40 LIGAND

Because CD40 ligand (CD40L) is a co-stimulator molecule for multiple c omponents of the immune response, we wanted to determine whether trans genic expression of the molecule would increase immune responses again st a weakly immunogenic murine tumor, neuro-2a, Tumor cells were trans duced with a retroviral construct-containing the CD40L gene and co-inj ected with variable numbers of non-CD40L transduced cells into syngene ic mice, Mice injected with cells that expressed CD40L had a significa nt 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 a ntitumor effects (p < 0.001), These antitumor effects protected mice f rom subsequent challenge with parental neuro-2a cells, The protective effects of CD40L were associated with systemic immunomodulation. In vi vo depletion of CD8(+) cells abrogated the CD40L-mediated antitumor ef fects, Analysis of spleens from CD40L-protected animals showed increas ed numbers of CD4(+) and CD8(+) cells, the majority of which co-expres sed the activation marker CD25, In addition, an increased number of an tigen-presenting cells (APCs) expressed the co-stimulatory molecule CD 86, These experiments illustrate that transducing even a small percent age of tumor cells with CD40 ligand can create a long-lasting systemic immune response capable of impeding growth of unmodified neuroblastom a cells.