Molecular mechanisms for tumor recognition and destruction by NK cells.

(1)我们发现a- galcer（一种NKT细胞的特异性激活剂）的抗转移作用不是由NKT细胞的细胞溶解活性介导的，而是由IFN-γ介导的，IFN-γ继发性激活NK细胞产生持续的IFN-γ。我们还发现TRAIL和抑制肿瘤血管生成是IFN-γ依赖的抗肿瘤效应因子机制。(2)我们发现NK细胞上的CD27和CD28对肿瘤细胞的CD70和CD80的识别不仅增强NK细胞介导的肿瘤排斥反应，而且以IFN-γ依赖的方式诱导肿瘤特异性CTL和Thl。(3)我们发现在肝脏NK细胞上表达的TRAIL在抑制肝脏肿瘤转移中起关键作用。我们还发现NK细胞中IFN-γ依赖性诱导TRAIL参与了IL-12和a-GalCer的抗转移作用。我们进一步发现TRAIL在p53+/-小鼠中NK细胞介导和IFN-γ- t依赖的免疫监视中对甲基胆碱诱导或自发肿瘤发展起关键作用。(4)我们发现，除了TRAIL和TNF外，TWEAK还参与了IFN-γ-凋亡单核细胞对肿瘤细胞的裂解。我们还发现，在一些肿瘤细胞中，TWEAK通过Fn14诱导caspase依赖性凋亡和组织蛋白酶b依赖性坏死，但不通过DR3。(5)我们发现，HLA-G的小鼠同源物囊胚MHC可以通过上调NK细胞上与CD94/NKG2A抑制受体结合的Qa-1b的表达，抑制NK细胞介导的tap缺陷肿瘤细胞的排斥反应。(6)我们发现，针对诱导死亡的小鼠TRAIL受体（mDR5）施用激动性单抗不仅可以诱导TRAIL敏感肿瘤的消退，还可以诱导肿瘤特异性CTL，该CTL也可以根除TRAIL耐药变体。

(1) We have revealed that the anti-metastatic effect of a-GalCer, a specific activator of NKT cells, is not mediated by cytolytic activity of NKT cells but by IFN-γ, which secondarily activates NK cells to produce sustained IFN-γ. We have also revealed TRAIL and suppression of tumor angiogenesis as the IFN-γ-dependent anti-tumor effctor mechanisms.(2) We have found that recognition of CD70 and CD80 on tumor cells by CD27 and CD28 on NK cells not only enhances NK cell-mediated tumor rejection but also induces tumor-specific CTL and Thl in an IFN-γ-dependent manner.(3) We have revealed that TRAIL expressed on hepatic NK cells plays a critical role in suppression of tumor metastasis in the liver. We have also revealed that IFN-γ-dependent induction of TRAIL in NK cells is involved in the anti-metastatic effects of IL-12 and a-GalCer. We have further revealed that TRAIL plays a pivotal role in the NK cell-mediated and IFN-γ-Tdependent immune surveilance against methylcholanthrene-ihduced or spontaneous tumor development in p53+/-mice.(4) We have revealed that TWEAK, as well as TRAIL and TNF, contrbutes to tumor cell lysis by IFN-γ-adivated monocytes. We have also revealed that TWEAK induces caspase-dependent apoptosis and cathepsin B-dependent necrosis in some tumor cells via Fn14 but not via DR3.(5) We have revealed that blastocyst MHC, a mouse homologue of HLA-G, can inhbi the NK cell-mediated rejection of TAP-deficient tumor cells by up-regulating the expression of Qa-1b, which engages CD94/NKG2A inhibitory receptor on NK cells.(6) We have found that administration of an agonistic mAb against a death-inducing mouse TRAIL receptor (mDR5) not only induces regression of TRAIL-sensitive tumors but also elicits tumor-specific CTL that can also eradicate TRAIL-resistant variants.