Mesenchymal stromal cells as carriers of IL-12 reduce primary and metastatic tumors of murine melanoma

Abstract

Due to immunosuppressive properties and confirmed tropism towards cancer cells mesenchymal stromal cells (MSC) have been used in many trials. In our study we used these cells as carriers of IL-12 in the treatment of mice with primary and metastatic B16-F10 melanomas. IL-12 has confirmed anti-cancer activity, induces a strong immune response against cancer cells and acts as an anti-angiogenic agent. A major limitation of the use of IL-12 in therapy is its systemic toxicity. The aim of the work was to develop a system in which cytokine may be administered intravenously without toxic side effects. In this study MSC were used as carriers of the IL-12. We confirmed antitumor effectiveness of the cells secreting IL-12 (MSC/IL-12) in primary and metastatic murine melanoma models. We observed inhibition of tumor growth and a significant reduction in the number of metastases in mice after MSC/IL-12 administration. MSC/IL-12 decreased vascular density and increased the number of anticancer M1 macrophages and CD8+ cytotoxic T lymphocytes in tumors of treated mice. To summarize, we showed that MSC are an effective, safe carrier of IL-12 cytokine. Administered systemically they exert therapeutic properties of IL-12 cytokine without toxicity. Therapeutic effect may be a result of pleiotropic (proinflammatory and anti-angiogenic) properties of IL-12 released by modified MSC.

TLR3 stimulation improves the migratory potency of adipose-derived mesenchymal stem cells through the stress response pathway in the melanoma mouse model

“…Some evidence supports the involvement of in ammatory signals in cancer as environmental cues in MSCs migration and biodistribution paradigm [15]. Previous research has shown that reducing tumor load and extending the lifespan of animal studies of melanoma, lung, breast cancer, and glioma using MSC expressing IL-12, interferon-β (IFN-β), and prodrugs [16][17][18].…”

Nanotechnology and bioengineering approaches to improve the potency of mesenchymal stem cell as an off‐the‐shelf versatile tumor delivery vehicle

“…25,26 MSCs can be easily genetically engineered and used as biofactory for the local production of chemo and biological anticancer therapeutics at the tumor sites to overcome the challenges related to the systemic administration of anticancer therapeutics with a short half-life or high toxicity. [26][27][28] MSCs have been used for the delivery of chemotherapeutics and biological anticancer therapeutics such as genes encoding prodrug-activating enzymes, 29,30 cytokines, 31,32 oncolytic viruses, 9,33 among others. Therefore, MSCs emerged as a versatile tumor delivery vehicle in precision cancer treatment technologies for different cancers.…”

“…Inflammation is a common feature of tumor tissues. 57 The tumor-tropism capability of MSCs toward several cancer cell lines such as melanoma, 31 colon cancer, 58 pancreatic cancer, 59 ovarian cancer, 60 breast cancer, 61 Kaposi's sarcoma, 20 lung cancer, 62 and malignant glioma 63 has been demonstrated. The tumor-tropism of MSCs is not limited to primary or solid tumors.…”

“…Several studies have reported that genetically engineered MSCs expressing cytokines can overcome the immunosuppressive condition in TME. To date, MSCs have been used as a vehicle for the selective delivery of a wide variety of cytokines, including IL‐2, 144 IL‐12, 31 IL‐18, 145,146 IFN‐α, 147 and Interferon beta (IFN‐β) 142 to various cancer models.…”

Antitumor Activities of Interleukin-12 in Melanoma

“…Intratumoral gene electroporation uses electric charges to help plasmid DNA enter target cells reproductively and effectively, especially in metastatic melanomas [ 33 ]. Other than gene electroporation, lipid nanoparticles [ 51 ], dual-targeting nanoparticles [ 80 ], hypoxia-responsive nanogel [ 81 ], cationic polyphosphazene vesicles [ 82 ], collagen [ 37 ] and heparin-based complex coacervate [ 23 ] were also developed to allow more efficient delivery as IL-12 or IL-12 encoding plasmid carrier, despite the artificial chemicals, mesenchymal stromal cells [ 83 ] and DCs [ 84 ] overexpressing IL-12 exert therapeutic properties of IL-12 cytokine without toxicity. Great efforts should be made in the future to further improve the anti-tumor efficacy and diminish the side effects of IL-12 therapy.…”