TGF-β 激活的 NK-92 细胞治疗食管鳞状细胞癌

Esophageal squamous cell carcinoma (ESCC) is the dominant histological type of esophageal cancer in China, with a poor outcome and limited treatment options. The cytotoxicity of natural killer (NK) cells, independent of specific antigen recognition, renders them a promising candidate for cell-based immunotherapy of cancers.

However, immunosuppressive cytokines, particularly TGF- , are highly expressed in the ESCC tumor microenvironment and exert strong inhibitory effects on NK cells. To address this challenge, we genetically modified a well-established human NK cell line, NK-92, to express extracellular and transmembrane domains of the TGF- receptor 2 along with 4-1BB costimulatory domain and CD3 (namely T4z chimeric receptor).

NK-92 cells expressing T4z receptor (NK-92-T4z cells) were resistant to TGF- -mediated suppressive signaling and even upregulated expression of NKG2D and perforin.

Notably, NK-92-T4z cells showed higher oxidative phosphorylation and glycolytic activity in the presence of TGF- . More importantly, NK-92-T4z cells displayed stronger cytotoxic activity against human ESCC cell lines in vitro, especially in a TGF- -rich environment.

Finally, adoptive transfer of NK-92-T4z cells reduced tumor growth in a xenograft ESCC model. These data suggest that converting inhibitory TGF- signals to activating signals in NK cells may represent a valuable therapeutic strategy for patients with ESCC.