Background: To overcome the limited proliferation of NKT cells from human peripheral blood for cancer immunotherapy, we developed human induced pluripotent stem (iPS) cell-derived NKT cells (iPS-NKT cells). However, we do not know if iPS-NKT cells have adjuvant activity like primary invariant NKT cells and demonstrate indirect cytotoxicity.
Methods: We prepared human IL-7 and IL-15 knock-in NSG mice inoculated with human peripheral blood mononuclear cells and patient-derived lung cancer. We administered iPS-NKT cells with or without αGalCer-loaded murine bone marrow-derived dendritic cells (DC/Gal). Tumor size was evaluated to assess the cytotoxicity. In addition, we collected human tumor-infiltrating lymphocytes (TILs) and performed single-cell RNA sequences to identify the mechanism of the anti-tumor effect.
Results: The combination therapy of iPS-NKT cells and DC/Gal significantly suppressed the tumor size. After the combination therapy, human TILs were proliferated and contained clonally expanded stem-like CD8 and CD4 T cells. The cytotoxicity was canceled when the stem-like T cells were depleted with an anti-CCR7 antibody. This indicated that the expanded stem-like T cells induced the cytotoxicity of the combination therapy.
Conclusion: Human iPS-NKT cells demonstrated an indirect anti-tumor effect by generating tumor-reactive stem-like T cells. Our result indicates that human iPS-NKT cells have the adjuvant activity of primary NKT cells.