A fundamental understanding of cancer-specific antigens is crucial for successful T-cell immunotherapy. Sarcoma antigen 1 (SAGE1) is a cancer/testis antigen that has not yet been verified for T-cell immunotherapy applications. Here, we examined SAGE1 RNA expression and carried out IHC analyses, revealing that SAGE1 is expressed in 50% of non–small cell lung-cancer samples (n = 40). To verify the immunogenicity of SAGE1, we discovered a novel HLA-A*24:02 (HLA-A24)–restricted SAGE1 epitope (SAGE1597–606, VFSTAPPAFI) using mass spectrometry and identified SAGE1597–606-specific T-cell clones and T-cell receptors (TCR) from peripheral bloods of HLA-A24+ donors. The highest affinity TCR VF3 (KD = 4.3 μM) demonstrated the highest antitumor potency. Moreover, VF3-transduced T cells mediated the efficient killing of HLA-A24+/SAGE1+ tumor cells in vitro and effectively inhibited the growth of lung cancer xenografts in mice. Together, our data suggest that SAGE1 could be a target for T-cell immunotherapies against lung cancer, while its specific TCRs could be candidates for developing reagents to treat SAGE1+ tumors.

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