Sabag Batel, Levy Moria, Kivelevitz Jessica, Dashevsky Nataly, Ben-Shmuel Aviad, Puthenveetil Abhishek, Awwad Fatima, Barda-Saad Mira
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 5290002, Israel.
Cancers (Basel). 2022 Aug 2;14(15):3756. doi: 10.3390/cancers14153756.
Understanding the crosstalk between natural killer (NK) cells and the tumor microenvironment (TME) has enhanced the potential of exploiting the interplay between activation and inhibition of NK cells for immunotherapy. This interaction is crucial for understanding how tumor cells escape NK cell immune surveillance. NK cell dysfunction is regulated by two molecular mechanisms, downregulated activating receptor ligand expression on the tumor cells, and upregulated inhibitory signals delivered to NK cells. Recent studies demonstrated the role of mechanotransduction in modulating NK cell responses in the TME. The immunological synapse represents a functional interface between the NK cell and its target, regulated by Actin Retrograde Flow (ARF), which drives the adhesion molecules and receptors toward the central zone of the immunological synapse (IS). Here, we further characterize the role of ARF in controlling the immune response of NK cells, using CRISPR/cas9-mediated Wiskott-Aldrich Syndrome protein (WASp) gene silencing of NK cells. We demonstrate that WASp regulates ARF velocity, affecting the conformation and function of the key NK inhibitory regulator, SH2-domain containing protein tyrosine phosphatase-1 (SHP-1), and consequently, the NK cell response. Our results demonstrate the potential of modulating the biophysical and intracellular regulation of NK activation as a promising approach for improving immunotherapy.
了解自然杀伤（NK）细胞与肿瘤微环境（TME）之间的相互作用，增强了利用NK细胞激活与抑制之间的相互作用进行免疫治疗的潜力。这种相互作用对于理解肿瘤细胞如何逃避NK细胞免疫监视至关重要。NK细胞功能障碍受两种分子机制调节，即肿瘤细胞上激活受体配体表达下调，以及传递给NK细胞的抑制信号上调。最近的研究证明了机械转导在调节TME中NK细胞反应中的作用。免疫突触代表NK细胞与其靶标之间的功能界面，由肌动蛋白逆行流（ARF）调节，ARF驱动粘附分子和受体向免疫突触（IS）的中心区域移动。在这里，我们使用CRISPR/cas9介导的NK细胞威斯科特-奥尔德里奇综合征蛋白（WASp）基因沉默，进一步表征了ARF在控制NK细胞免疫反应中的作用。我们证明WASp调节ARF速度，影响关键NK抑制调节因子含SH2结构域的蛋白酪氨酸磷酸酶-1（SHP-1）的构象和功能，从而影响NK细胞反应。我们的结果表明，调节NK激活的生物物理和细胞内调节作为一种改善免疫治疗的有前景的方法具有潜力。
