Dendritic cells (DCs) are the most effective antigen-presenting cells (APCs), and play a central role in the induction of anticancer adaptive immunity. Our recent studies have led to novel findings that human DCs are not only crucial APCs of tumor-associated antigens (TAAs) but also potent anticancer effectors that are able to selectively induce apoptosis in cancer cells using multiple TNF family ligands (TNFfLs). Following this killing, DCs phagocytize the resulting apoptotic bodies and efficiently induce cross-priming of cancer-specific cytotoxic T lymphocytes (CTLs). Our preliminary studies indicate that DCs of HNC patients have decreased cell surface expression of TNFfLs and impaired anticancer apoptotic activity. Our additional data suggest that these defects of DCs are caused by increased shedding of the ligands due to the activation of DC metalloproteinases (MPs). These defects of DCs might be a major cause of cancer escape from immune control in HNC patients. In this application, we plan to test the hypothesis that DCs of HNC patients have defective cell surface expression of TNFfLs and impaired abilities to kill autologous cancer cells and initially process cellular TAAs. We predict that these molecular and functional defects of DCs will be correctable by restoration of their cell membrane TNFfLs. The resulted restoration of apoptotic activity of DCs will improve DC-mediated direct elimination of cancer cells, processing of TAAs and ultimate cross-priming of anticancer CTLs. These functional changes of DOs should lead to substantial augmentation of host anticancer immune functions and control of cancer growth. The hypothesis will be tested in a series of in vitro experiments followed by preclinical animal studies, as defined in the following Specific Aims. 1) To define defects of apoptotic killing of HNC cells and related immune functions in HNC patients; 2) To investigate whether these DC defects are mediated by HNC and/or cytokines via activation of MPs; 3) To assess whether the defective apoptotic activity and related functions of DCs of HNC patients can be repaired by restoring cell membrane-bound cytotoxic TNFfLs using transfer of the ligand genes; and 4) To determine the biological and clinical significance of DC-mediated tumoricidal activity by assessing in vivo the use of this DC activity in prevention and therapy of syngeneic squamous cell carcinoma in mice. The proposed study will define biological and clinical relevance of DC tumoricidal activity and is likely to lead to development of more potent DC-based vaccines for prevention and therapy of HNC.
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