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Select groups of premalignant oral lesions carry a high risk of development of secondary premalignant lesions and oral squamous cell carcinoma (OSCC). The goal of the present study was to determine the feasibility of using premalignant lesion-pulsed dendritic cells as a treatment option to prevent development of secondary lesions and development of OSCC. Mice that were treated with the carcinogen 4-nitroquinoline-1-oxide (4NQO) developed premalignant oral lesions and, subsequently, OSCC. Immunohistochemical analyses showed that these 4NQO-induced lesions and OSCC both overexpressed the tumor antigens epidermal growth factor receptor, RAGE and, to a lesser extent, MUC1. Because there was shared overexpression of tumor antigens on premalignant oral lesions and OSCC, dendritic cells pulsed with lysates of 4NQO-induced premalignant lesion cells were tested in vitro and in vivo for their capacity to stimulate T-cell reactivity to premalignant lesion cells and to OSCC. Spleen cells that were sensitized during coculture or in vivo with premalignant lesion-pulsed dendritic cells were cytolytic toward both premalignant lesion cells and OSCC, and secreted increased levels of interferon -γ in response to challenge with premalignant lesion cells or OSCC as compared with spleen cells that were sensitized with keratinocyte-pulsed dendritic cells. Levels of CD8+ Tcells and interferon-γ release were also increased in lesions of mice that were vaccinated with premalignant lesion-pulsed dendritic cells. The mice that were vaccinated against premalignant lesions were also more resistant to OSCC challenge. These studies show the feasibility of using premalignant oral lesions to stimulate immune reactivity against both premalignant oral lesions and OSCC.