Abstract MAGED4B is a member of the Melanoma Antigen Gene (MAGE) family. We demonstrated that MAGED4B is over-expressed in more than 50% of oral squamous cell carcinoma (OSCC) tissues and that the expression of MAGED4B is associated with lymph node metastasis and poor disease specific survival. OSCC cell lines over-expressing MAGED4B exhibited an increase in cell growth both in vitro and in vivo, and were significantly more resistant to UV-induced apoptosis compared to control cells, suggesting a role for MAGED4B in modulating cell death. Further, MAGED4B also promoted cell migration. MAGE proteins are good targets for cancer immunotherapy as they are highly immunogenic. We identified and synthesized MAGED4B peptides that were HLA-A2- specific and tested the ability of these peptides to generate an anti-tumour response using PBMCs from OSCC patients and healthy individuals. Firstly, the PBMC samples obtained from patients and healthy individuals were tested for HLA-A2 expression. Positive samples were analyzed for peptide-specific stimulation of IFN-γ and granzyme secretion ex-vivo via ELISPOT assay. Dendritic cells pulsed with these peptides were used to stimulate PBMC cultures, and were studied for IFN-γ and granzyme secretion. In parallel, the binding of the peptides to the MHC-Class I molecule was determined by the binding assay. Further, the ability of these bound peptides to interact with T cells was measured by the dimer assay. We demonstrated that all the peptides have good binding capacity with the MHC-Class I molecules. Moreover, the binding of these peptides on MHC-Class I molecules could attract and further interact with T cells. Notably, the PBMC stimulated once with peptide-pulsed dendritic cells or twice with peptide and peptide-pulsed dendritic cells showed peptide-specific cytotoxic activity against MAGED4B-expressing OSCC cell lines. In summary, we first demonstrated that MAGED4B drives oral carcinogenesis and second, showed that MAGED4B-specific peptides are apable of inducing anti-tumour specific immune responses. Taken together, this indicates that MAGED4B could be a promising peptide vaccine target for the treatment of OSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1573. doi:1538-7445.AM2012-1573