EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells
EGFR-Specific Tyrosine Kinase Inhibitor Modifies NK Cell-Mediated Antitumoral Activity against Ovarian Cancer Cells
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DOI：
10.3390/ijms20194693
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发表时间：
2019-10-01
影响因子：
5.6
通讯作者：
Brandau, Sven
中科院分区：
文献类型：
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作者：
Mallmann-Gottschalk, Nina;Sax, Yvonne;Brandau, Sven
大多数卵巢癌患者的不良预后与化疗和靶向治疗耐药引起的复发有关。单克隆抗体和酪氨酸激酶抑制剂（TKI）除了直接对抗肿瘤细胞外，还影响免疫细胞的抗肿瘤活性，这对免疫疗法的设计具有重要意义。在这项临床前研究中，我们用抗表皮生长因子受体（EGFR）TKI治疗不同的卵巢癌细胞系，并将其与自然杀伤（NK）细胞共孵育。我们研究了在抗EGFR抗体西妥昔单抗存在下肿瘤和免疫细胞的治疗相关结构和功能变化，并研究了NK介导的抗肿瘤活性。我们发现，卵巢癌细胞长期暴露于TKI会导致内在敏感癌细胞的反应性随时间推移而降低。然而，无论是TKI还是西妥昔单抗的长期治疗都不能克服某些卵巢癌细胞对抗EGFR药物的内在耐药性。值得注意的是，用抗EGFR TKI预处理的肿瘤细胞显示出对NK细胞介导的抗体依赖性细胞毒性（ADCC）的敏感性增加。相反，TKI致敏降低了NK细胞的细胞因子分泌。我们的数据表明，抗EGFR TKI对肿瘤细胞的致敏作用差异性地调节了与NK细胞的相互作用。这些数据对设计该肿瘤实体的化学免疫组合疗法具有重要意义。
The adverse prognosis of most patients with ovarian cancer is related to recurrent disease caused by resistance to chemotherapeutic and targeted therapeutics. Besides their direct activity against tumor cells, monoclonal antibodies and tyrosine kinase inhibitors (TKIs) also influence the antitumoral activity of immune cells, which has important implications for the design of immunotherapies. In this preclinical study, we treated different ovarian cancer cell lines with anti-epidermal growth factor receptor (EGFR) TKIs and co-incubated them with natural killer (NK) cells. We studied treatment-related structural and functional changes on tumor and immune cells in the presence of the anti-EGFR antibody cetuximab and investigated NK-mediated antitumoral activity. We show that long-term exposure of ovarian cancer cells to TKIs leads to reduced responsiveness of intrinsically sensitive cancer cells over time. Inversely, neither long-term treatment with TKIs nor cetuximab could overcome the intrinsic resistance of certain ovarian cancer cells to anti-EGFR agents. Remarkably, tumor cells pretreated with anti-EGFR TKIs showed increased sensitivity towards NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In contrast, the cytokine secretion of NK cells was reduced by TKI sensitization. Our data suggest that sensitization of tumor cells by anti-EGFR TKIs differentially modulates interactions with NK cells. These data have important implications for the design of chemo-immuno combination therapies in this tumor entity.