Fluid shear stress enhances natural killer cell's cytotoxicity toward circulating tumor cells through NKG2D-mediated mechanosensing.

IF 6.6 3区 医学 Q1 ENGINEERING, BIOMEDICAL
Bing Hu, Ying Xin, Guanshuo Hu, Keming Li, Youhua Tan
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Abstract

Tumor cells metastasize to distant organs mainly via hematogenous dissemination, in which circulating tumor cells (CTCs) are relatively vulnerable, and eliminating these cells has great potential to prevent metastasis. In vasculature, natural killer (NK) cells are the major effector lymphocytes for efficient killing of CTCs under fluid shear stress (FSS), which is an important mechanical cue in tumor metastasis. However, the influence of FSS on the cytotoxicity of NK cells against CTCs remains elusive. We report that the death rate of CTCs under both NK cells and FSS is much higher than the combined death induced by either NK cells or FSS, suggesting that FSS may enhance NK cell's cytotoxicity. This death increment is elicited by shear-induced NK activation and granzyme B entry into target cells rather than the death ligand TRAIL or secreted cytokines TNF-α and IFN-γ. When NK cells form conjugates with CTCs or adhere to MICA-coated substrates, NK cell activating receptor NKG2D can directly sense FSS to induce NK activation and degranulation. These findings reveal the promotive effect of FSS on NK cell's cytotoxicity toward CTCs, thus providing new insight into immune surveillance of CTCs within circulation.

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流体剪切应力通过nkg2d介导的机械感应增强自然杀伤细胞对循环肿瘤细胞的细胞毒性。
肿瘤细胞主要通过血液播散向远处器官转移,其中循环肿瘤细胞(循环肿瘤细胞)相对脆弱,消除循环肿瘤细胞具有很大的防止转移的潜力。在血管系统中,自然杀伤细胞(NK)是在流体剪切应力(FSS)作用下有效杀伤CTCs的主要效应淋巴细胞,是肿瘤转移的重要机械提示。然而,FSS对NK细胞抗ctc细胞毒性的影响尚不清楚。我们报道了NK细胞和FSS共同作用下CTCs的死亡率远高于NK细胞或FSS联合作用导致的死亡率,这表明FSS可能增强NK细胞的细胞毒性。这种死亡增加是由剪切诱导的NK活化和颗粒酶B进入靶细胞引起的,而不是死亡配体TRAIL或分泌的细胞因子TNF-α和IFN-γ引起的。当NK细胞与ctc结合或粘附在mica包被的底物上时,NK细胞激活受体NKG2D可直接感知FSS,诱导NK细胞活化和脱颗粒。这些发现揭示了FSS对NK细胞对ctc的细胞毒性的促进作用,从而为循环中ctc的免疫监测提供了新的见解。
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来源期刊
APL Bioengineering
APL Bioengineering ENGINEERING, BIOMEDICAL-
CiteScore
9.30
自引率
6.70%
发文量
39
审稿时长
19 weeks
期刊介绍: APL Bioengineering is devoted to research at the intersection of biology, physics, and engineering. The journal publishes high-impact manuscripts specific to the understanding and advancement of physics and engineering of biological systems. APL Bioengineering is the new home for the bioengineering and biomedical research communities. APL Bioengineering publishes original research articles, reviews, and perspectives. Topical coverage includes: -Biofabrication and Bioprinting -Biomedical Materials, Sensors, and Imaging -Engineered Living Systems -Cell and Tissue Engineering -Regenerative Medicine -Molecular, Cell, and Tissue Biomechanics -Systems Biology and Computational Biology
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