Molecular mechanisms for tumor recognition and destruction by NK cells.

NK 细胞识别和破坏肿瘤的分子机制。

• 批准号: 13214096
• 负责人: YAGITA Hideo
• 金额: $ 27.26万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-13214096/
• 关键词: NK cells; tumor; immune surveillance; TRAIL; DR5; TWEAK; activating receptor; inhibitory receptor; NKT細胞; ICOS; CD94; NKG2A; 転移; アポトーシス; ネクローシス; IFN-γ; CTL; 免疫監視機構; 発癌; CD27; CD70

(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.

(1)我们已经揭示，α-GalCer（NKT细胞的特异性活化剂）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次级活化NK细胞以产生持续的IFN-γ。我们还揭示了TRAIL和抑制肿瘤血管生成是IFN-γ依赖的抗肿瘤效应机制。(2)我们已经发现，NK细胞上的CD 27和CD 28识别肿瘤细胞上的CD 70和CD 80不仅增强NK细胞介导的肿瘤排斥，而且以IFN-γ依赖的方式诱导肿瘤特异性CTL和Thl。(3)我们已经揭示了在肝NK细胞上表达的TRAIL在抑制肝中的肿瘤转移中起关键作用。我们还揭示了NK细胞中TRAIL的IFN-γ依赖性诱导参与IL-12和α-GalCer的抗转移作用。我们进一步揭示了TRAIL在NK细胞介导的和IFN-γ-T依赖的对甲基胆蒽诱导的或自发的p53+/-小鼠肿瘤发展的免疫监视中起关键作用。(4)我们已经发现，TWEAK，以及TRAIL和TNF，有助于IFN-γ诱导的单核细胞溶解肿瘤细胞。我们还发现，TWEAK诱导半胱天冬酶依赖性凋亡和组织蛋白酶B依赖性坏死的一些肿瘤细胞通过Fn 14，但不通过DR 3。(5)我们已经发现，囊胚MHC，一种HLA-G的小鼠同源物，可以通过上调Qa-1b的表达来抑制NK细胞介导的对TAP缺陷肿瘤细胞的排斥反应，Qa-1b结合NK细胞上的CD 94/NKG 2A抑制性受体。(6)我们已经发现，针对死亡诱导小鼠TRAIL受体（mDR 5）的激动性mAb的施用不仅诱导TRAIL敏感性肿瘤的消退，而且还诱导肿瘤特异性CTL，其也可以根除TRAIL抗性变体。

项目成果

Hayakawa, Y.: "IFN-γ-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, α-galactosylceramide"Blood. 100. 1728-1733 (2002)

Hayakawa，Y.：“自然杀伤 T 细胞配体 α-半乳糖苷神经酰胺对干扰素-γ 介导的肿瘤血管生成的抑制”血液。100。1728-1733 (2002)

Kelly, J.M.: "Induction of tumor-specific T cell memory by NK cell-midiated tumor rejection."Nature Immunol.. 3. 83-90 (2002)

Kelly, J.M.：“NK 细胞介导的肿瘤排斥诱导肿瘤特异性 T 细胞记忆。”《自然免疫学》3. 83-90 (2002)

Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy

• DOI: 10.1084/jem.20031457
• 发表时间: 2004-02-16
• 期刊: JOURNAL OF EXPERIMENTAL MEDICINE
• 影响因子: 15.3
• 作者: Takeda, K;Yamaguchi, N;Smyth, MJ
• 通讯作者: Smyth, MJ

Induction of tumor-specific T cell memory by NK cell-mediated tumor rejection

• DOI: 10.1038/ni746
• 发表时间: 2002-01-01
• 期刊: NATURE IMMUNOLOGY
• 影响因子: 30.5
• 作者: Kelly, JM;Darcy, PK;Smyth, MJ
• 通讯作者: Smyth, MJ

TRAIL contributes to IFN-γ-dependent NK cell protection from tumor metastasis.

TRAIL 有助于 IFN-γ 依赖性 NK 细胞保护免受肿瘤转移。

• 发表时间: 2001
• 期刊: J.Exp.Med. 193
• 作者: Smyth;M.J.
• 通讯作者: M.J.