Abstract
Polyplex micelles have demonstrated biocompatibility and achieve efficient gene transfection in vivo. Here, we investigated a polyplex micelle encapsulating genes encoding the tumor-associated antigen squamous cell carcinoma antigen recognized by T cells-3 (SART3), adjuvant CD40L, and granulocyte macrophage colony-stimulating factor (GM-CSF) as a DNA vaccine platform in mouse tumor models with different types of major histocompatibility antigen complex (MHC). Intraperitoneally administrated polyplex micelles were predominantly found in the lymph nodes, spleen, and liver. Compared with mock controls, the triple gene vaccine significantly prolonged the survival of mice harboring peritoneal dissemination of CT26 colorectal cancer cells, of which long-term surviving mice showed complete rejection when re-challenged with CT26 tumors. Moreover, the DNA vaccine inhibited the growth and metastasis of subcutaneous CT26 and Lewis lung tumors in BALB/c and C57BL/6 mice, respectively, which represent different MHC haplotypes. The DNA vaccine highly stimulated both cytotoxic T lymphocyte and natural killer cell activities, and increased the infiltration of CD11c+ DCs and CD4+/CD8a+ T cells into tumors. Depletion of CD4+ or CD8a+ T cells by neutralizing antibodies deteriorated the anti-tumor efficacy of the DNA vaccine. In conclusion, a SART3/CD40L+GM-CSF gene-loaded polyplex micelle can be applied as a novel vaccine platform to elicit tumor rejection immunity regardless of the recipient MHC haplotype.
Highlights
Cancer vaccines have attracted attention as a promising modality to treat patients with malignancies, because they elicit specific rejection immunity against tumor-associated antigens (TAAs) with minimal invasiveness to normal tissues in contrast to chemotherapy, irradiation, and surgery
During vaccination, fragmented TAA peptides bound to the major histocompatibility complex (MHC) expressed by antigen-presenting cells (APCs), such as dendritic cells (DCs), [1] stimulate naive T lymphocytes to mature into helper and cytotoxic T lymphocytes (CTLs) in concert with co-stimulatory signals via the B7/CD28 interaction [2]
Infiltration of CD4+ and CD8a+ T cells into tumors is increased by DNA vaccine treatment We examined the infiltration of CD4+/CD8a+ T cells into tumor tissues after administration of SART3/CD40L+Granulocyte macrophage colony-stimulating factor (GM-CSF) gene-loaded polyplex micelles by immunohistochemical analysis (Fig. 6A)
Summary
Cancer vaccines have attracted attention as a promising modality to treat patients with malignancies, because they elicit specific rejection immunity against tumor-associated antigens (TAAs) with minimal invasiveness to normal tissues in contrast to chemotherapy, irradiation, and surgery. During vaccination, fragmented TAA peptides bound to the major histocompatibility complex (MHC) expressed by antigen-presenting cells (APCs), such as dendritic cells (DCs), [1] stimulate naive T lymphocytes to mature into helper and cytotoxic T lymphocytes (CTLs) in concert with co-stimulatory signals via the B7/CD28 interaction [2]. Peptide-, cell- and gene-based vaccines have been applied for treatment of cancer and infection diseases in animal models and human clinical trials. For cell-based vaccines, TAA genes are transduced into DCs or autologous tumor cells ex vivo using viral vectors. Cell-based vaccines allow co-expression of TAA and adjuvant genes to induce more efficient rejection of weakly immunogenic TAAs. For example, GM-CSF- and CD40L-expressing DC vaccines have been evaluated in clinical trials [9]. Whether direct transduction of these adjuvant genes affects the immunological response and contributes to TAAspecific tumor rejection in vivo is unknown
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