Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.
Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.
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DOI：
10.1038/s42003-021-02440-3
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发表时间：
2021-07-22
影响因子：
5.9
通讯作者：
Wu JD
中科院分区：
文献类型：
--
作者：
Dhar P;Basher F;Ji Z;Huang L;Qin S;Wainwright DA;Robinson J;Hagler S;Zhou J;MacKay S;Wu JD
自然杀伤（NK）细胞功能障碍与癌症患者较差的临床预后相关。肿瘤微环境中调控NK细胞功能障碍的机制尚不清楚。在这里，我们证明了人类肿瘤来源的NKG2D配体可溶性MIC （sMIC）重编程NK细胞分泌促肿瘤细胞因子，降低细胞毒性和多功能潜能。抗体清除sMIC使NK细胞恢复到正常的细胞毒效应功能状态。我们发现sMIC选择性地激活NK细胞中的cbm信号体炎症途径。相反，肿瘤细胞膜结合MIC （mMIC）通过激活PLC2γ2/SLP-76/Vav1通路刺激NK细胞的细胞毒性。最终，靶向sMIC的抗体实现了过继转移NK细胞的体内抗肿瘤作用。我们的发现揭示了一种未被认识的机制，该机制可以指示NK细胞响应肿瘤微环境中的线索而进入功能失调状态。我们的研究结果为共同靶向sMIC以增强正在进行的基于NK细胞的癌症免疫治疗的疗效提供了理论依据。Dhar等人使用原代人和小鼠自然杀伤（NK）细胞证明，肿瘤来源的NKG2D配体可溶性MIC （sMIC）可以重编程NK细胞，使其分泌促肿瘤细胞因子，降低细胞毒性和多功能潜能。他们的研究为共同靶向sMIC提供了理论基础，以增强当前基于NK细胞的癌症免疫治疗。
Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transferred NK cells. Our findings uncover an unrecognized mechanism that could instruct NK cell to a dysfunctional state in response to cues in the tumor microenvironment. Our findings provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy. Dhar et al used primary human and mouse natural killer (NK) cells to demonstrate that tumor-derived NKG2D ligand soluble MIC (sMIC) can reprogram the NK cells to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Their study provides a rationale for co-targeting sMIC in order to enhance current NK cell-based cancer immunotherapies.
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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：
7
作者：
Dhar P;Wu JD
通讯作者：
Wu JD
DOI：
10.1073/pnas.201238598
发表时间：
2001-09-25
影响因子：
11.1
作者：
Cerwenka, A;Baron, JL;Lanier, LL
通讯作者：
Lanier, LL
DOI：
10.1073/pnas.0611655104
发表时间：
2007-04-10
影响因子：
11.1
作者：
Chen, Xi;Trivedi, Prachi P.;Strominger, Jack L.
通讯作者：
Strominger, Jack L.
影响因子：
20.3
作者：
Caraux, A;Kim, N;Colucci, F
通讯作者：
Colucci, F