Harnessing the Antiviral-Type Responses Induced by Immunostimulatory siRNAs for Cancer Immunotherapy

Abstract

When introduced into endosomes via cationic lipids, certain small interfering RNA (siRNA) sequences activate the interferon signaling pathways in immune cells such as dendritic cells (DCs), known as the most efficient antigen-presenting cells of the immune system. Human immature DCs produced high levels of the immune-response protein interferon-α and tumor necrosis factor- α upon incubation with siRNA/lipid formulations, resulting in their maturation and expression of co-stimulatory molecules like CD80, CD86, and CD40 on the cell surface. These molecules are used by mature DCs to co-stimulate T cells during antigen presentation in lymphoid organs. Ex vivo loading of immature DCs with DOTAP-formulated immunostimulatory siRNAs and tumor antigens has proven effective as a cancer vaccine in a rat model of acute myeloid leukemia. Here, we describe this new vaccination strategy that targets tumor cells by activating DCs and blocking the expression of immunosuppressive factors.