Genetically Modified Murine Adipose-Derived Mesenchymal Stem Cells Producing Interleukin-2 Favor B16F10 Melanoma Cell Proliferation

Abstract

Adipose-derived mesenchymal stem cells (ADSCs) are attractive tools for cancer gene therapy due to their intrinsic tropism to the tumor environment. Interleukin-2 (IL2) is recognized as a key regulatory molecule, which enhances the activity and growth of the immune effector cell function. High-Dose IL2 Therapy is an option for treatment of malignant melanoma but has frequent, often serious and sometimes life-threatening side effects. Here we investigated the effect of genetically modified ADSCs (GM-ADSCs) expressing IL2 in immunocompetent mouse models of subcutaneous and lung metastatic melanoma. Prior to in vivo studies, we demonstrated that IL2 produced by GM-ADSCs may act as a growth factor for melanoma cells due to the increased viability and reduced apoptosis of melanoma cells after in vitro treatment. Subcutaneous co-injection of IL2-expressing ADSCs with melanoma cells significantly enhanced the melanoma tumor growth. Furthermore, histological analysis of subcutaneous tumors for IL2 and Melan-A (a melanocytic differentiation marker) confirmed that most of cells in melanoma/IL2-ADSC co-injected tumors are melanoma cells, not IL2-ADSCs. In pulmonary metastases model, melanoma cells were injected intravenously and 10 days later mice were treated by systematical injection of GM-ADSCs. Intravenously injected IL2-ADSCs engrafted into melanoma lung tumors but were unable to reduce melanoma lung metastases. Besides, administered IL2-ADSCs significantly reduced systemic CD4+ cells and did not impact the total survival of lung metastases melanoma bearing mice. In conclusion, this study showed that IL2-producing ADSCs can favor B16F10 melanoma cell proliferation. Therefore, therapies utilizing IL2 have to be taken into careful consideration.

• Adipose-derived mesenchymal stem cell (ADSC)
• interleukin-2 (IL2)
• melanoma B16F10
• T regulatory (Treg) cell

Acknowledgements

We express appreciation to Dr. Yousef Gheisari for helpful technical advice and discussions. We would also like to thank Dr. Michele Calos for generous gifts of pBEB, pBLB, and pCMVInt.

This research was supported by Grant 189048 from the Isfahan University of Medical Sciences.

Declaration of interest

The sponsor had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the article and the decision to submit the article for publication. Authors declare no conflicts of interest.