IL-12 Enhances Immune Response by Modulation of Myeloid Derived Suppressor Cells in Tumor Microenvironment / 전남의대학술지

Myeloid derived suppressor cells (MDSCs) are a heterogenous population of immature cells that play a critical role in tumor associated immune suppression. In tumor conditions, the population of MDSCs increases. The main feature of these cells is their ability to suppress the T cell response in antigen specific or nonspecific manners depending on the condition of T cell activation. IL-12 can modulate MDSC in preliminary reports, so we investigated how IL-12 can affect MDSC in a tumor microenvironment. After implanting tumor based cells on syngeneic host, 4T-1/BALB/c or EL4/C57BL6 mice, MDSCs (Gr1+CD11b+) were isolated from splenocytes. Isolated MDSCs were treated with GM-CSF with or without IL-12 and analyzed based on their phenotypes and functions. Treatment of MDSC with IL-12 increased co-stimulatory molecules of CD80, CD86, OX-40L, enhancing the DC phenotype (CD11c) and maturation markers such as p-NF-κB and p-GSK3β. In addition to a change of surface markers, T-cell suppressive function of MDSC after IL-12 treatment was significantly improved compared with the control MDSC. In addition, PD-L1+F4/80+ macrophages, which show aninhibitory effect in phagocytosis, were decreased after IL-12 treatment. The changes of cell surface expression of CD80, CD86, MHC class II were also shown in vivo. Our results showed that the IL-12 can modulate MDSC into APC and recover the macrophage function. These results suggested that IL-12 plays a role in improving the tumor immune microenvironment through MDSC modulation.

Gene Therapy for Head and Neck Squamous Cell Carcinoma Using KITENIN (KAI1 COOH-Terminal Interacting Tetraspanin)-Antisense Therapy

PURPOSE: KAI1 COOH-terminal interacting tetraspanin (KITENIN) has been found to act as a promoter of metastasis in murine models of colon cancer and squamous cell carcinoma (SCC). The suppression of tumor progression and metastasis of established colon cancer in mice was observed after intravenous delivery of small interfering RNA (siRNA) targeting KITENIN. The purpose of this study was to investigate the efficacy of gene therapy targeting KITENIN in human head and neck SCC. MATERIALS AND METHODS: SNU-1041, a well-established human hypopharyngeal SCC cell line, was used. KITENIN expression in SNU-1041 was measured by Western blot analysis. The cells were prepared, maintained in culture dishes with media, and divided into two groups: the si-KITENIN group and the scrambled group (control). The siRNA targeting KITENIN (si-KITENIN) and scrambled DNA were transfected into the SNU-1041 cells in each group. The effect of gene therapy was compared by in vitro experiments to evaluate invasion, migration, and proliferation. RESULTS: KITENIN was strongly expressed in the SNU-1041 cells, and the number of invaded cells was reduced more in the si-KITENIN group than in the scrambled group (p<0.001). The speed for the narrowing gap, made through adherent cells, was lower in the si-KITENIN group (p<0.001), and the number of viable proliferating cells was reduced in the si-KITENIN group compared to the scrambled group (p<0.001, the third day). KITENIN protein expression was no longer identified in the si-KITENIN group. CONCLUSION: Gene therapy using an anti-KITENIN strategy might be effective for head and neck squamous carcinoma.