The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.
The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.
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DOI：
10.3390/biomedicines12010196
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发表时间：
2024-01-16
期刊：
影响因子：
4.7
通讯作者：
Wu, Jennifer D.
中科院分区：
文献类型：
--
作者：
Serritella, Anthony V.;Saenz-Lopez Larrocha, Pablo;Dhar, Payal;Liu, Sizhe;Medd, Milan M.;Jia, Shengxian;Cao, Qi;Wu, Jennifer D.
NKG2D是人类所有NK细胞和CD8 T细胞表达的激活受体。利用NKG2D/NKG2D配体轴已成为癌症免疫治疗的可行途径。然而，关于可溶性NKG2D配体是免疫抑制还是免疫刺激，长期存在争议，这源于不同范围的临床前研究中产生的相互矛盾的数据。通过使用多个临床前肿瘤模型，我们证明了最具特征的人类实体肿瘤相关可溶性NKG2D配体，可溶性MHC I链相关分子（sMIC）对肿瘤发生的影响取决于所研究的肿瘤模型以及肿瘤细胞是否具有干细胞样特性。我们证明了肿瘤形成或建立的潜力取决于肿瘤细胞干细胞样特性，而不管肿瘤细胞分泌可溶性NKG2D配体sMIC。具体而言，如果表达smic的肿瘤细胞表达低干细胞标记物，则肿瘤形成延迟或失败；如果表达smic的肿瘤细胞表达高干细胞样细胞标记物，则肿瘤形成迅速。然而，一旦肿瘤形成，过表达sMIC明确抑制肿瘤NK和CD8 T细胞免疫，促进肿瘤生长。我们的研究区分了可溶性NKG2D配体在肿瘤形成和肿瘤进展中的不同影响，澄清了可溶性NKG2D配体在调节肿瘤免疫方面的突出争议，并加强了靶向可溶性NKG2D配体用于肿瘤免疫治疗的可行性。
NKG2D is an activating receptor expressed by all human NK cells and CD8 T cells. Harnessing the NKG2D/NKG2D ligand axis has emerged as a viable avenue for cancer immunotherapy. However, there is a long-standing controversy over whether soluble NKG2D ligands are immunosuppressive or immunostimulatory, originating from conflicting data generated from different scopes of pre-clinical investigations. Using multiple pre-clinical tumor models, we demonstrated that the impact of the most characterized human solid tumor-associated soluble NKG2D ligand, the soluble MHC I chain-related molecule (sMIC), on tumorigenesis depended on the tumor model being studied and whether the tumor cells possessed stemness-like properties. We demonstrated that the potential of tumor formation or establishment depended upon tumor cell stem-like properties irrespective of tumor cells secreting the soluble NKG2D ligand sMIC. Specifically, tumor formation was delayed or failed if sMIC-expressing tumor cells expressed low stem-cell markers; tumor formation was rapid if sMIC-expressing tumor cells expressed high stem-like cell markers. However, once tumors were formed, overexpression of sMIC unequivocally suppressed tumoral NK and CD8 T cell immunity and facilitated tumor growth. Our study distinguished the differential impacts of soluble NKG2D ligands in tumor formation and tumor progression, cleared the outstanding controversy over soluble NKG2D ligands in modulating tumor immunity, and re-enforced the viability of targeting soluble NKG2D ligands for cancer immunotherapy for established tumors.
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DOI：
10.1126/science.aao0505
发表时间：
2018-03-30
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ferrari de Andrade L;Tay RE;Pan D;Luoma AM;Ito Y;Badrinath S;Tsoucas D;Franz B;May KF Jr;Harvey CJ;Kobold S;Pyrdol JW;Yoon C;Yuan GC;Hodi FS;Dranoff G;Wucherpfennig KW
通讯作者：
Wucherpfennig KW
影响因子：
3.8
作者：
Arai, Jun;Otoyama, Yumi;Fujita, Ken-ichi;Goto, Kaku;Tojo, Masayuki;Katagiri, Atsushi;Nozawa, Hisako;Kubota, Yutaro;Takahashi, Takehiro;Ishida, Hiroo;Tsunoda, Takuya;Matsumoto, Natsumi;Ogawa, Keita;Nakagawa, Ryo;Muroyama, Ryosuke;Kato, Naoya;Yoshida, Hitoshi
通讯作者：
Yoshida, Hitoshi
CD166通过EGFR/ERK1/2通路在鼻咽癌细胞系CNE-2R中促进癌症干细胞样表型
影响因子：
6.1
作者：
Chen, Xishan;Liang, Renba;Zhu, Xiaodong
通讯作者：
Zhu, Xiaodong
影响因子：
5.9
作者：
Dhar P;Basher F;Ji Z;Huang L;Qin S;Wainwright DA;Robinson J;Hagler S;Zhou J;MacKay S;Wu JD
通讯作者：
Wu JD
影响因子：
6.4
作者：
Holdenrieder, S;Stieber, P;Salih, HR
通讯作者：
Salih, HR