Pluripotent stem cell-derived siTNK cells attack tumors via a synthetic CD8-CD28 TCR complex
Zheng, X.; Zhang, F.; Lin, Y.; Hu, F.; Weng, Q.; Liu, P.; Wang, Z.; Zhang, C.; Liu, Y.; Liu, L.; Zhu, Y.; Xiao, Z.; Wang, Y.; Zhang, L.; Qi, H.; Shen, Y.; Chen, Y.; Wu, J.; Xu, J.; Zhao, Y.; Wang, T.; Huang, D.; Xia, C.; Wang, J.; Zhang, M.
Show abstract
Tumor-associated antigen-specific T cell receptor (TCR)-engineered T cells offer a promising strategy for cancer therapy. Natural killer (NK) cells exhibit broad anti-tumor activity with low side effects but lack the capacity to recognize intracellular antigens. Here, we found that the human pluripotent stem cell (hPSC)-derived iNK cells, unlike tissue-isolated NK cells, expressed all four CD3 subunits at the transcriptome level. We introduced a synthetic gene-expressing complex (SCOTR), encoding a tumor antigen- specific TCR, CD8 coreceptor, and CD28 costimulatory molecule, into hPSCs to generate SCOTR-hPSCs. The SCOTR-hPSCs gave rise to abundant synthetic TCR complex-expressing iNK (siTNK) cells via an organoid induction method. These siTNK cells showed HLA-dependent, antigen-specific cytotoxicity against tumor cells and significantly suppressed tumor growth in tumor xenograft animal models, while also preserving universal non-specific tumor-killing activity. Collectively, siTNK cells, as hPSC-derived hybrid cells with dual features of adaptive T and inherent NK cells, offer an artificial cell source for human immunotherapies.
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