Abstract
Abstract Interleukin 12 (IL-12) is a heterodimeric cytokine encoded by two genes, p35 and p40. IL-12, also known as T cell-stimulating factor, induces proliferation of T-lymphocytes and natural killer (NK) cells, while also demonstrating an anti-angiogenic effect and inhibition of regulatory T cells. Similarly, LIGHT (TNFSF14) is a transmembrane protein which acts as a costimulatory factor for the activation lymphoid cells and stimulates the proliferation of T cells, leading to increased apoptosis of tumor cells. Expression of IL-12 and LIGHT specifically in the tumor region could activate T cells and stimulate the immune system to attenuate the tumor. Tumor homing neuronal stem cells C17.2 (NSC) were genetically engineered to express the mouse-LIGHT gene and IL-12 using a retrovirus. The expression of LIGHT and IL-12 genes in NSC was confirmed by PCR, ELISA and Western blot. To test the antitumor effects of the engineered cells, Balb/C mice bearing 4T1 mammary tumors were treated with NSC-LIGHT, NSC-IL-12 and NSC-LIGHT/IL-12 cells intratumorally (I.T.) at day nine. Repeated tumor measurement over time showed attenuation of mammary tumor growth in the both NSC/IL-12 and NSC/LIGHT groups in comparison with control groups PBS and NSC. Tumor growth was further reduced by treating the mice with NSC expressing both cytokines LIGHT and IL-12. Tumor metastasis was also evaluated by removing the primary tumor surgically and observing mice for any sign of metastatic burden. Treatment groups had less metastatic tumor burden and survived longer than the control group. Therefore, tumor homing NPC-LIGHT/IL-12 cells could be effective for the treatment of highly metastatic mammary tumors. Citation Format: Tej B. Shrestha, Dezhang Lu, Matthew T. Basel, Marla Pyle, Stefan H. Bossmann, Deryl L. Troyer. Genetically modified neuronal stem cells expressing IL-12 and TNFSF14 attenuate highly metastatic mammary tumors in a mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1613. doi:10.1158/1538-7445.AM2017-1613
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