Inhibition Growth and Metastasis of Melanoma by 4-1BBL Expressed in Normal Tissue Cells by Regulating the Function of Immune Cells

Abstract

Many tumor immunotherapy efforts are focused on upregulating the expression of 4-1BB/4-1BBL by transferring genes into immune cells or tumor cells. In this study, we sought to study whether 4-1BBL, expressed in normal tissue cells, inhibits the growth and metastasis of tumor. The expressing plasmid, p4-1BBL, was constructed and was used to treat established melanoma in situ model and metastasis tumor model mice, respectively, with injecting directly into the skeletal muscle of the inoculation site and systemically administering plasmid with the hydrodynamics-based gene-delivery approach. Administration of p4-1BBL resulted in high-level expression in the muscle and liver. Treatment of tumor-bearing mice with 4-1BBL plasmid DNA significantly suppressed the growth and metastasis of melanoma without significant toxicity, compared with mice treated with control-plasmid DNA. This treatment with plasmid p4-1BBL in vivo induced an infiltration of CD8⁺ T-cells into the tumor milieu and an increase of levels of interleukin-2 and interferon-gamma. Our study suggests that 4-1BBL expressed in normal tissue cells has significant antitumor activity and may have therapeutic potential as an antitumor agent in the clinic. Directly intramuscular injection peritumor and hydrodynamic intravenous injection may provide promising immune gene-therapy approaches for different tumor clinical stages.