阻断 TIGIT-CD155/CD112 轴可增强 NK-92 细胞的功能，但对细胞因子诱导的记忆样 NK 细胞针对表达 CD155 的急性髓系白血病的作用无增强效果

TIGIT is an alternative checkpoint receptor (CR) whose inhibition promotes Graft-versus-Leukemia effects of NK cells. Given the significant immune-permissiveness of NK cells circulating in acute myeloid leukemia (AML) patients, we asked whether adoptive transfer of activated NK cells would benefit from additional TIGIT-blockade. Hence, we characterized cytokine-induced memory-like (CIML)-NK cells and NK cell lines for the expression of inhibitory CRs.

In addition, we analyzed the transcription of CR ligands in AML patients (CCLE and Beat AML 2. 0 cohort) in silico and evaluated the efficacy of CR blockade using in vitro cytotoxicity assays, CD69, CD107a and IFN-γ expression.

Alternative but not classical CRs were abundantly expressed on healthy donor NK cells and even further upregulated on CIML-NK cells. In line with our finding that CD155, one important TIGIT-ligand, is reliably expressed on AMLs, we show improved killing of CD155 + -AML blasts by NK-92 but interestingly not CIML-NK cells in the presence of TIGIT-blockade.

Additionally, our in silico data (n = 671) show that poor prognosis AML patients rather displayed a CD86 low CD112/CD155 high phenotype, whereas patients with a better outcome rather exhibited a CD86 high CD112/CD155 low phenotype. Collectively, our data evidence that the complex CR ligand expression profile on AML blasts may be one explanation for the intrinsic NK cell exhaustion observed in AML patients which might be overcome with adoptive NK-92 transfer in combination with TIGIT-blockade.