Abstract
High-dose recombinant interleukin 2 (IL2) therapy has been shown to be successful in renal cell carcinoma and metastatic melanoma. However, systemic administration of high doses of IL2 can be toxic, causing capillary leakage syndrome and stimulating pro-tumor immune response. One of the strategies to reduce the systemic toxicity of IL2 is the use of mesenchymal stem cells (MSCs) as a vehicle for the targeted delivery of IL2. Human adipose tissue-derived MSCs were transduced with lentivirus encoding IL2 (hADSCs-IL2) or blue fluorescent protein (BFP) (hADSCs-BFP). The proliferation, immunophenotype, cytokine profile and ultrastructure of hADSCs-IL2 and hADSCs-BFP were determined. The effect of hADSCs on activation of peripheral blood mononuclear cells (PBMCs) and proliferation and viability of SH-SY5Y neuroblastoma cells after co-culture with native hADSCs, hADSCs-BFP or hADSCs-IL2 on plastic and Matrigel was evaluated. Ultrastructure and cytokine production by hADSCs-IL2 showed modest changes in comparison with hADSCs and hADSCs-BFP. Conditioned medium from hADSC-IL2 affected tumor cell proliferation, increasing the proliferation of SH-SY5Y cells and also increasing the number of late-activated T-cells, natural killer (NK) cells, NKT-cells and activated T-killers. Conversely, hADSC-IL2 co-culture led to a decrease in SH-SY5Y proliferation on plastic and Matrigel. These data show that hADSCs-IL2 can reduce SH-SY5Y proliferation and activate PBMCs in vitro. However, IL2-mediated therapeutic effects of hADSCs could be offset by the increased expression of pro-oncogenes, as well as the natural ability of hADSCs to promote the progression of some tumors.
Highlights
Interleukin 2 (IL2) is one of the first cytokines which, along with interferon α (IFN-α), was used for the treatment of cancer [1]
LV-IL2 or LV-blue fluorescent protein (BFP) were added at a multiplicity of infection (MOI) of 10 to human adipose tissue-derived MSCs line (hADSCs) (50% confluency) and cells were cultured with the virus in serum-free Dulbecco’s modified Eagle medium (DMEM)/F12 for 6 h
The use of mesenchymal stem cells (MSCs) as a vehicle for the delivery of therapeutic agents can increase the effectiveness of IL2-based immunotherapy by stimulating an antitumor immune response or directly inhibiting tumor growth
Summary
Interleukin 2 (IL2) is one of the first cytokines which, along with interferon α (IFN-α), was used for the treatment of cancer [1]. Contrasting reports support a tumor suppressive role for MSCs in breast cancer [32], Kaposi’s sarcoma [33] and pancreatic cancer [34], potentially through inhibition of the PI3K/AKT pathway and activation of other pathways leading to cell-cycle arrest and apoptosis [35]. These data suggest the effect of MSCs on tumor growth and development depends on various molecules produced by MSCs, the mechanisms of double-edged effect of MSCs are yet to be fully understood.
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