Development and characterization of naive single-type tumor antigen-specific CD8⁺ T lymphocytes from murine pluripotent stem cells

ABSTRACT

Optimal approaches to differentiate tumor antigen-specific cytotoxic T lymphocytes (CTLs) from pluripotent stem cells (PSCs) remain elusive. In the current study, we showed that combination of in vitro priming through Notch ligands and in vivo development facilitated the generation of tumor Ag-specific CTLs that effectively inhibited tumor growth. We co-cultured the murine induced PSCs (iPSCs) genetically modified with tyrosinase-related protein 2 (TRP2)-specific T cell receptors with OP9 cell line expressing both Notch ligands Delta-like 1 and 4 (OP9-DL1/DL4) for a week before adoptively transferred into recipient C67BL/6 mice. Three weeks later, B16 melanoma cells were inoculated subcutaneously, and the antitumor activity of the iPSC-derived T cells was assessed. We observed the development of the TRP2-specific iPSC-CD8⁺ T cells that responded to Ag stimulation and infiltrated into melanoma tissues, significantly inhibited the tumor growth, and improved the survival of the tumor-bearing mice. Thus, this approach may provide a novel effective strategy to treatment of malignant tumors.

KEYWORDS:

• Cytotoxic T lymphocytes
• immunotherapy
• melanoma, mouse
• Pluripotent stem cells

Disclosure of potential conflicts of interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors thank Dr Arthur A. Hurwitz from National Cancer Institute for providing TRP2-specific TCR genes.

Funding

This project was funded, in part, by grants from National Institute of Health Grant R01AI121180, R21AI109239, and R21AI128325, and the American Diabetes Association (1–16-IBS-281) to J.S.