Tseng Han-Ching, Cacalano Nicholas, Jewett Anahid
Division of Oral Biology and Oral Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, Los Angeles, CA, USA.
Department of Radiation Oncology, Division of Molecular and Cellular Oncology UCLA School of Medicine, Los Angeles, CA, USA.
Oncotarget. 2015 Apr 20;6(11):8947-59. doi: 10.18632/oncotarget.3250.
The mechanism of suppression of NK cytotoxicity in cancer patients is not clearly established. In this paper we provide evidence that anergized NK cells induce differentiation of healthy Dental Pulp Stem Cells (DPSCs) or transformed Oral Squamous Cancer Stem Cells (OSCSCs) resulting in cell growth inhibition, resistance to NK cell-mediated cytotoxicity and prevention of inflammatory mediators secretion. Induction of cytotoxicity resistance in differentiated cells correlated with increased CD54 and MHC class I surface expression and mediated by the combination of IFN-γ and TNF-α since antibodies to both, but not each cytokine alone, was able to inhibit resistance. In contrast, inhibition of cytokine and chemokine release was mediated by IFN-γ since the addition of anti-IFN-γ antibody, and not anti-TNF-α, restored secretion of inflammatory mediators in NK cell cultures with differentiated DPSCs and OSCSCs. There was a gradual and time dependent decrease in MHC class I and CD54 expression which correlated with the restoration of NK cell cytotoxicity, augmentation of cytokine secretion and increased cell growth from days 0-12 post NK removal. Continuous presence of NK cells is required for the maintenance of cell differentiation since the removal of NK cell-mediated function reverses the phenotype and function of differentiated cells to their stem-like cells.
癌症患者中自然杀伤细胞（NK）细胞毒性受抑制的机制尚未明确确立。在本文中，我们提供证据表明，失能的NK细胞可诱导健康牙髓干细胞（DPSC）或转化的口腔鳞状癌干细胞（OSCSC）分化，从而导致细胞生长抑制、对NK细胞介导的细胞毒性产生抗性以及防止炎症介质分泌。分化细胞中细胞毒性抗性的诱导与CD54和MHC I类分子表面表达增加相关，且由IFN-γ和TNF-α共同介导，因为针对这两种细胞因子而非单独每种细胞因子的抗体能够抑制抗性。相比之下，细胞因子和趋化因子释放的抑制由IFN-γ介导，因为添加抗IFN-γ抗体而非抗TNF-α抗体可恢复与分化的DPSC和OSCSC共培养的NK细胞培养物中炎症介质的分泌。从去除NK细胞后的第0 - 12天，MHC I类分子和CD54表达逐渐且呈时间依赖性下降，这与NK细胞细胞毒性的恢复、细胞因子分泌增加以及细胞生长增加相关。维持细胞分化需要NK细胞持续存在，因为去除NK细胞介导的功能会使分化细胞的表型和功能逆转回其干细胞样状态。
