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.
Grossmann
M E
ME
Division of Bone Marrow Transplantation and Cell and Gene Therapy Program, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Brown
M P
MP
Brenner
M K
MK
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006651:Histocytochemistry; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D009447:Neuroblastoma / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D012190:Retroviridae / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology; D019076:Transgenes; D014407:Tumor Cells, Cultured
D008562:Membrane Glycoproteins; D023201:CD40 Ligand