Kaur Kawaljit, Celis Angie Perez, Jewett Anahid
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, 10833 Le Conte Ave, Los Angeles, CA 90095, USA.
The Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cells. 2025 Jan 10;14(2):90. doi: 10.3390/cells14020090.
We demonstrate that natural killer (NK) cells induce a higher cytotoxicity against lung cancer stem-like cells (hA549) compared to differentiated lung cancer cell lines (H292). The supernatants from split-anergized NK cells (IL-2 and anti-CD16 mAb-treated NK cells) induced differentiation in hA549. Differentiated lung cancer cell line (H292) and NK cells differentiated hA549 expressed reduced NK cell-mediated cytotoxicity but expressed higher sensitivity to chemotherapeutic drugs. This finding validated our previous reports demonstrating that the levels of tumor killing by NK cells and by chemotherapeutic drugs correlate directly and indirectly, respectively, with the stage and levels of tumor differentiation. We also demonstrate the role of IFN-γ and TNF-α in inducing tumor differentiation. NK cells' supernatants or IFN-γ and TNF-α-induced tumor differentiation was blocked when we used antibodies against IFN-γ and TNF-α. Therefore, IFN-γ and TNF-α released from NK cells play a significant role in differentiating tumors, resulting in increased susceptibility of tumors to chemotherapeutic drugs. We also observed the different effects of MHC-class I antibodies in CSCs vs. differentiated tumors. Treatment with anti-MHC-class I decreased NK cell-mediated cytotoxicity in hA549 tumors, whereas it increased NK cell-mediated cytotoxicity when differentiated tumors were treated with antibodies against MHC-class I.
我们证明，与分化的肺癌细胞系（H292）相比，自然杀伤（NK）细胞对肺癌干细胞样细胞（hA549）具有更高的细胞毒性。来自分裂无反应性NK细胞（IL-2和抗CD16单克隆抗体处理的NK细胞）的上清液可诱导hA549分化。分化的肺癌细胞系（H292）和经NK细胞分化的hA549表现出降低的NK细胞介导的细胞毒性，但对化疗药物表现出更高的敏感性。这一发现证实了我们之前的报告，即NK细胞和化疗药物的肿瘤杀伤水平分别与肿瘤分化的阶段和水平直接和间接相关。我们还证明了IFN-γ和TNF-α在诱导肿瘤分化中的作用。当我们使用抗IFN-γ和TNF-α的抗体时，NK细胞的上清液或IFN-γ和TNF-α诱导的肿瘤分化被阻断。因此，NK细胞释放的IFN-γ和TNF-α在肿瘤分化中起重要作用，导致肿瘤对化疗药物的敏感性增加。我们还观察到MHC-I类抗体在癌症干细胞与分化肿瘤中的不同作用。用抗MHC-I类抗体处理可降低hA549肿瘤中NK细胞介导的细胞毒性，而当用抗MHC-I类抗体处理分化肿瘤时，可增加NK细胞介导的细胞毒性。
