Invariant natural killer T (NKT) cells exhibit strong antitumor immunity by producing large amounts of cytokines, such as IFN-γ, and directly mediate tumoricidal activity. NKT cells express invariant T cell receptors (TCRs) to recognize their cognate glycolipid antigen, such as α-galactosylceramide (α-GalCer) presented on CD1d. NKT cells can target and kill tumor cells, which express CD1d, whereas A549 cells, the lung adenocarcinoma cell line, do not express CD1d and are resistant to NKT cell-mediated cytotoxicity.
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor, a therapeutic target of non-small cell lung cancer (NSCLC). TCGA analysis indicated a higher expression level of the ERBB2 gene, which encodes HER2, in lung tumor tissues compared to healthy lungs. Therefore, we hypothesized that the HER2/CD3 bispecific antibody (bsAb) brings NKT cells close to lung cancer cells, thus triggering the direct killing of tumor cells. A549 cells expressed relatively low levels of HER2. NKT cells pretreated with HER2/CD3 bsAb showed cytotoxicity against A549 cells and produced cytokines, including IFN-γ. Furthermore, NKT cells pretreated with HER2/CD3 bsAb suppressed A549 growth in vivo mouse model. These data implicate that HER2/CD3 bsAb treatment can augment NKT cell-based immunotherapy to treat lung cancer.