Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma

Abstract 

Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to cancer. The cytokine interleukin-12 (IL-12) has demonstrated a potent anti-tumor activity in a variety of mouse tumor models. In this study, human MSCs were isolated from human bone marrow and identified by phenotype analysis and differentiation assays. The anti-tumor activity of human MSCs stably transduced with a recombinant adenoviral vector expressing the murine IL-12 (MSC/IL-12) were evaluated in a mouse xenograft model of renal cell carcinoma (RCC). Expression and bioactivity of the transgenic protein IL-12 from adenoviral vector were confirmed prior to in vivo studies. A nude mouse model of RCC was developed by subcutaneously injection of 786-0 cells into nude mice. MSC/IL-12 was injected into the lateral tail vein with single dose. Results indicated that systemic administration of MSC/IL-12 reduced the growth of 786-0 RCC and significantly prolonged mouse survival. These transfected cells could home to tumors after intravenous injection and largely produce local IL-12 protein. In contrast, systemic level of IL-12 was modestly elevated. Further studies showed that the anti-tumor activity of the MSC/IL-12 was dependent on the presence of natural killer (NK) cells and IFN-γ in this experimental setting. These data demonstrate the potential of adult MSC constitutively producing IL-12 to reduce the growth of RCC and enhance the tumor-bearing mouse survival.

Abbreviations: CMV, cytomegalovirus, IL-12, interleukin-12, MSC, mesenchymal stem cell, rAAV, recombinant adeno-associated virus, GFP, green fluorescent protein, RCC, renal cell carcinoma

Keywords: Mesenchymal stem cells, Interleukin-12, Renal cell carcinoma, Gene therapy