ABSTRACT
PURPOSE: The invention and application of new immunotherapeutic methods can compensate for the inefficiency of conventional cancer treatment approaches, partly due to the inhibitory microenvironment of the tumor. In this study, we tried to inhibit the growth of cancer cells and induce anti-tumor immune responses by silencing the expression of the ß-catenin in the tumor microenvironment and transmitting interleukin (IL)-15 cytokine to provide optimal conditions for the dendritic cell (DC) vaccine. METHODS: For this purpose, we used folic acid (FA)-conjugated SPION-carboxymethyl dextran (CMD) chitosan (C) nanoparticles (NPs) to deliver anti-ß-catenin siRNA and IL-15 to cancer cells. RESULTS: The results showed that the codelivery of ß-catenin siRNA and IL-15 significantly reduced the growth of cancer cells and increased the immune response. The treatment also considerably stimulated the performance of the DC vaccine in triggering anti-tumor immunity, which inhibited tumor development and increased survival in mice in two different cancer models. CONCLUSIONS: These findings suggest that the use of new nanocarriers such as SPION-C-CMD-FA could be an effective way to use as a novel combination therapy consisting of ß-catenin siRNA, IL-15, and DC vaccine to treat cancer.
Subject(s)
Antineoplastic Agents/administration & dosage , Cancer Vaccines/administration & dosage , Dendritic Cells/transplantation , Drug Carriers , Interleukin-15/administration & dosage , Magnetic Iron Oxide Nanoparticles , Melanoma, Experimental/therapy , RNA, Small Interfering/administration & dosage , RNAi Therapeutics , Skin Neoplasms/therapy , beta Catenin/genetics , Animals , Antineoplastic Agents/chemistry , Cancer Vaccines/immunology , Cell Line, Tumor , Cell Proliferation/drug effects , Dendritic Cells/immunology , Drug Compounding , Female , Gene Expression Regulation, Neoplastic , Interleukin-15/chemistry , Lymphocytes, Tumor-Infiltrating/immunology , Melanoma, Experimental/genetics , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice, Inbred BALB C , RNA, Small Interfering/genetics , Skin Neoplasms/genetics , Skin Neoplasms/immunology , Skin Neoplasms/pathology , Tumor Burden/drug effects , Tumor MicroenvironmentABSTRACT
PURPOSE: T-cell immunoglobulin and ITIM domain (TIGIT) is an immune checkpoint that is overexpressed on both immune cells and some cancer cells. TIGIT can alter the anti-tumor responses inside the tumor microenvironment. Hypoxia-inducible factor 1-alpha (HIF-1α) plays a significant role in the TME and involves suppressing the anti-tumor responses. Under hypoxic conditions, HIF-1α can enhance the expression of different immune checkpoints. Accordingly, hypoxic TME and TIGIT overexpression cause cancer development. Thus, we decided to inhibit tumor cell expansion by inhibiting TIGIT and HIF-1α molecules and discovering the relationship between TIGIT and HIF-1α. METHODS: In this research, we utilized superparamagnetic iron oxide-based NPs (SPIONs) combined with chitosan lactate (CL) and folic acid (FA) nanoparticles (NPs) loaded with TIGIT-siRNA and HIF-1α- siRNA for suppressing TIGIT and HIF-1α in tumor cells and evaluated the consequences of this treatment strategy on tumor growth, apoptosis, and metastasis. RESULTS: The results showed that cancer cells treated with TIGIT and HIF-1α siRNA-loaded SPIONs-CL-FA NPs, strongly suppressed the TIGIT and HIF-1α expression, colony formation ability, angiogenesis, and the growth rate of cancer cells. CONCLUSIONS: Present data suggest the combination treatment of TIGIT and HIF-1α as a novel treatment strategy against colorectal and breast cancer, but more researches are required to realize the complete role of TIGIT and HIF-1α inside the TME.
