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Although recent therapeutic approaches have revitalized the enthusiasm of the immunological way to combat cancer, still the comprehension of the immunity against tumors is largely incomplete. Due to their specific function, CD8+ T cells with cytolytic activity (CTL) have attracted the attention of most investigators because CTL are considered the main effectors against tumor cells. Nevertheless, CTL activity and persistence are largely dependent on the action of CD4+ T helper cells (TH). Thus establishment of tumorspecific TH cell response is key to the optimal response against cancer. I will describe emerging new strategies to increase the TH cell recognition of tumor antigens. In particular, I will present recent data indicating that tumor cells themselves can act as surrogate antigen presenting cells for triggering TH response if genetically modified to express the MHC class II transcriptional activator CIITA. Indeed, injection of CIITA-modified tumor cells of distinct histological origin and of distinct MHC genetic background into syngeneic recipients induces strong protective and long-lasting adaptive immune response that can be transferred to naive recipients by CD4+ TH cells. Depletion of dendritic cells does not modify the capacity to reject the tumor and to acquire immunological memory. These results challenge the immunological dogma that dendritic cells are the exclusive cells capable of inducing T cell priming. The strategy of modifying tumor cells with CIITA has been applied for the production of a novel generation of anti-tumor vaccine against human hepatocarcinoma that is now in clinical trial.