Natural killer cells play a critical role in the immune response following immunization with melanoma-antigen-engineered dendritic cells

Abstract

Tumor antigen gene-modified dendritic cells (DC) generates robust antigen-specific protective antitumor responses. Though the role of CD4 positive and CD8 positive cells in the immunological response to gene-modified DC has been well-characterized, the role of NK cells in this response has been somewhat less clear. Owing to the significant contribution of innate immunity in other model systems, we postulated that NK cells would hold a critical position in the generation of an immune response following immunization with tumor antigen-engineered DC. Immunization with MART-1 melanoma antigen-engineered DC in C57BL/6 mice resulted in the generation of antigen-specific cytotoxic T lymphocytes and in vivo protective responses to the murine B16 melanoma. These responses were dependent on the presence of functional NK cells, although NK cells alone were not sufficient in generating protective responses. Adoptive transfer of NK cells into an NK-deficient but T-cell-competent environment restored the protective response to gene-modified DC immunization. In conclusion, protective immunity after tumor antigen gene-modified DC immunization requires collaboration between CD4 þ and CD8 þ T cells and NK cells.

Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15

“…by guest www.bloodjournal.org From observation that NKp30 is up-regulated on NK cells stimulated with DCs, suggest that Ad.DCs and mDC-mediated increases in NK-cell antitumor activity are mediated via up-regulation of NK-cell cytotoxic molecules and activating receptors. These DCinduced NK-cell functions may regulate the quality and extent of anticancer innate and adaptive immune responses 25 and have remarkable biologic significance and anticancer therapeutic potential.…”

“…[22][23][24] The effectiveness of Ad.DC-based vaccines may be dependent on the ability of Ad.DCs to crosstalk with NK cells and bridge innate and adaptive immunity. 25 However, it has not yet been investigated whether and how Ad.DCs interact with NK cells.…”

Adenoviral Gene Transfer of Stromal Cell–Derived Factor-1 to Murine Tumors Induces the Accumulation of Dendritic Cells and Suppresses Tumor Growth

“…Several strategies have been developed to use dendritic cells to augment antitumor immune responses, including pulsing dendritic cells with tumor peptides or RNA and gene transfer of tumor antigens into dendritic cells (34)(35)(36)(37). Dendritic cells can be genetically modified in vitro with adenovirus or retrovirus vectors encoding tumor-associated antigens, including the h-galactosidase gene as a model antigen (28,38,39), MART-1 (40)(41)(42), and epithelial cell mucin-1 (43), and the administration of these modified dendritic cells induce antigen-specific antitumor immune responses. Intratumoral injection of dendritic cells transduced with CD40 ligand results in sustained tumor regression (44).…”

Adenovirus MART-1–engineered Autologous Dendritic Cell Vaccine for Metastatic Melanoma

“…[34][35][36][37] In murine models testing E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)-transduced DC vaccines, we have identified a critical role for NK cells. 38 NK function has not yet been studied in human antigen-engineered DC clinical trials.…”

“…[34][35][36][37][43][44][45] Our own results in a murine model of AdVMART1/DC-based immunization support a functional role for NK cells in antitumor responses to this vaccination strategy. 38 We therefore tested patient lymphocytes for NK phenotype to determine whether the AdVMART1/DC vaccines had an impact on NK cells in vivo. We followed both CD56 hi /CD16 neg (regulatory or cytokine-producing) and Figure 6.…”