The Utility of Poly(.GAMMA.-glutamic acid) Nanoparticles as Antigen Delivery Carriers in Dendritic Cell-Based Cancer Immunotherapy

Abstract

The efficacies of cancer immunotherapy approaches are determined by their ability to induce tumor-specific cytotoxic T-lymphocytes (CTLs), which are major effector cells in tumor immunity. One approach to fighting cancer that is gaining popularity among tumor immunologists is immunization of cancer patients with autologous dendritic cells (DCs) loaded ex vivo with tumor-associated antigens (TAAs). 1)DCs are unique professional antigen-presenting cells (APCs) capable of priming CTLs and helper T cells (Th) by presenting antigens via major histocompatibility complex (MHC) class I and II molecules, followed by co-stimulatory signals. In this regard, an essential event in the generation of effective tumor immunity is the efficient display of antigenic fragments by MHC class I molecules, which can prime and expand CTLs on the surface of manipulated DCs for immunization. MHC class I-presented peptides are usually derived from endogenous antigens synthesized by cells, including DCs. Antigens in the extracellular fluids do not gain access to the MHC class I-pathway in most cells and thus fail to be presented. DCs are capable of presenting exogenous antigens on MHC class I molecules in a process that is called "crosspresentation," and this process is markedly enhanced when the antigen is internalized by phagocytosis, 2) macropinocytosis, 3) or receptor-mediated endocytosis. 4,5) Therefore, the development of a non-cytotoxic and efficient method to deliver antigens to the MHC class I-pathway in DCs is essential for improving the efficacy of DC-based cancer immunotherapy.Immature DCs situated in peripheral tissues serve as sentinels to immunologic threats and actively internalize particulate antigens such as bacteria and viruses.6,7) Based on this characteristic, the particulate antigen delivery system is thought to be ideal for generating cross-presentation in DCs. We developed biodegradable nanoparticles comprising amphiphilic poly(g-glutamic acid) (g-PGA NPs) that can efficiently entrap various proteins. We previously reported that DCs loaded with g-PGA NPs containing entrapped antigens enhance antigen presentation via MHC class I molecules by delivering the antigens to the DC cytosol. 8,9) It was unclear, however, whether g-PGA NPs affect DC maturation, and whether DCs loaded with TAA using g-PGA NPs more effectively induce TAA-specific CTL production and the anti-tumor response. Thus, in the present study, we investigated the characteristics and utility of g-PGA NPs as antigen delivery carriers in DC-based cancer immunotherapy. MATERIALS AND METHODSMice and Cells Female C57BL/6 mice (7 weeks of age) were purchased from Japan SLC Inc. (Hamamatsu, Japan). OT-I T cell receptor-transgenic mice specific for ovalbumin (OVA) (257)(258)(259)(260)(261)(262)(263)(264) presented by H-2K b and OT-II T cell receptortransgenic mice specific for OVA (323)(324)(325)(326)(327)(328)(329)(330)(331)(332)(333)(334)(335)(336)(337)(338)(339) presented by I-A b were purchased from Jackson Laboratory (Bar Harbor, ME, U.S.A.). Animal experimen...

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