Department of Gynecology and Obstetrics, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
Department of Otorhinolaryngology, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
Int J Mol Sci. 2019 Sep 22;20(19):4693. doi: 10.3390/ijms20194693.
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.
大多数卵巢癌患者预后不良，这与化疗和靶向治疗耐药导致的疾病复发有关。除了直接针对肿瘤细胞的活性外，单克隆抗体和酪氨酸激酶抑制剂（TKIs）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）TKIs 处理不同的卵巢癌细胞系，并与自然杀伤（NK）细胞共孵育。我们研究了在抗 EGFR 抗体西妥昔单抗存在的情况下，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逐渐降低。相反，长期 TKI 治疗或西妥昔单抗均不能克服某些卵巢癌细胞对 EGFR 抑制剂的内在耐药性。值得注意的是，用抗 EGFR TKI 预处理的肿瘤细胞对 NK 细胞介导的抗体依赖性细胞毒性（ADCC）表现出更高的敏感性。相比之下，TKI 敏化会降低 NK 细胞的细胞因子分泌。我们的数据表明，抗 EGFR TKI 对肿瘤细胞的敏化会以不同的方式调节与 NK 细胞的相互作用。这些数据对该肿瘤实体的化疗免疫联合治疗方案的设计具有重要意义。
