Impaired NK cytotoxicity has been linked to poor cancer prognosis, but its mechanisms are not clearly established. Increasing data demonstrate that NK cells lose cytotoxicity after interaction with NK cell-sensitive tumor cells. In this paper, we provide evidence that the human adenocarcinoma cell line MiaPaCa2 and TNFα and TGFβ-treated MiaPaCa2 cultures (MiaPaCa2-TT) induced functional anergy of NK cells via FGL2 protein. MiaPaCa2-TT cultures decreased expression of IFNγ, CD107a, DNAM-1, and stimulated expression of PD1 by NK cells, as well as inhibited their cytotoxic activity in a greater manner compared to the parental culture. More importantly, we found that co-cultivation with anergized NK cells decreased expression of IFNγ and CD107a by naïve NK cells, which supports the hypothesis of NK cell functional anergy transmission. The obtained results suggest a mechanism by which tumor cells may inhibit cytotoxic functions of tumor-infiltrating and circulating NK cells in cancer.

Abbreviations

CFSE: Carboxyfluorescein diacetate succinimidyl ester; CSCs: Cancer stem cells; FGL2: Fibrinogen-like protein 2; mAbs: Monoclonal antibodies; MiaPaCa2: Human adenocarcinoma cell line; MiaPaCa2-ТТ: Adenocarcinoma cell line MiaPaCa2 cells stimulated with TNFα and TGFβ-1; PI: Propidium iodide; TGFβ: Transforming growth factor beta; TME: Tumor microenvironment; TNFα: Tumor necrosis factor alfa

中文翻译：

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Fc 受体参与 Miapaca2 肿瘤细胞系诱导的 Nk 细胞功能性无反应。

NK细胞毒性受损与癌症预后不良有关，但其机制尚不清楚。越来越多的数据表明，NK 细胞在与 NK 细胞敏感的肿瘤细胞相互作用后会失去细胞毒性。在本文中，我们提供证据表明人腺癌细胞系 MiaPaCa2 和 TNFα 和 TGFβ 处理的 MiaPaCa2 培养物 (MiaPaCa2-TT)通过以下途径诱导 NK 细胞的功能性无反应。FGL2 蛋白。与亲本培养相比，MiaPaCa2-TT 培养物降低了 IFNγ、CD107a、DNAM-1 的表达，并刺激了 NK 细胞的 PD1 表达，并以更大的方式抑制了它们的细胞毒活性。更重要的是，我们发现与失能的 NK 细胞共培养降低了幼稚 NK 细胞的 IFNγ 和 CD107a 的表达，这支持了 NK 细胞功能性无能传递的假设。获得的结果表明肿瘤细胞可能抑制癌症中肿瘤浸润和循环 NK 细胞的细胞毒性功能的机制。

缩写

CFSE：羧基荧光素二乙酸琥珀酰亚胺酯；CSCs：癌症干细胞；FGL2：纤维蛋白原样蛋白 2；mAbs：单克隆抗体；MiaPaCa2：人腺癌细胞系；MiaPaCa2-ТТ：用 TNFα 和 TGFβ-1 刺激的腺癌细胞系 MiaPaCa2 细胞；PI：碘化丙啶；TGFβ：转化生长因子β；TME：肿瘤微环境；TNFα：肿瘤坏死因子α