Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu, 42472, South Korea.
Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, South Korea.
Sci Rep. 2022 May 23;12(1):8652. doi: 10.1038/s41598-022-12692-6.
Cancer immunoediting drives the adaptation of tumor cells to host immune surveillance. Previously, we have demonstrated that immunoediting driven by cytotoxic T lymphocytes (CTLs) enriches NANOG tumor cells with immune-refractory properties. Here, we found that CTL-mediated immune pressure triggered cross-resistance of tumor cells to the complement system, a part of the innate immune system. In this process, NANOG upregulated the membrane-bound complement regulatory protein (mCRP) CD59 through promoter occupancy, thereby contributing to the resistance of tumor cells against complement-dependent cytotoxicity (CDC). Notably, targeting of NANOG sensitized the immune-refractory tumor cells to trastuzumab-mediated CDC. Collectively, our results revealed a possible mechanism through which selection imposed by T-cell based immunotherapy triggered complement-resistant phenotypes in the tumor microenvironment (TME), by establishing a firm molecular link between NANOG and CD59 in immune-edited tumor cells. We believe these results hold important implications for the clinical application of CDC-mediated therapeutic antibody.
癌症免疫编辑促使肿瘤细胞适应宿主免疫监视。此前，我们已经证明，细胞毒性 T 淋巴细胞 (CTL) 驱动的免疫编辑使 NANOG 肿瘤细胞具有免疫抵抗特性。在这里，我们发现 CTL 介导的免疫压力触发了肿瘤细胞对补体系统的交叉耐药性，补体系统是先天免疫系统的一部分。在这个过程中，NANOG 通过启动子占据而上调膜结合补体调节蛋白 (mCRP) CD59，从而有助于肿瘤细胞抵抗补体依赖性细胞毒性 (CDC)。值得注意的是，靶向 NANOG 使免疫抵抗的肿瘤细胞对曲妥珠单抗介导的 CDC 敏感。总之，我们的研究结果揭示了一种可能的机制，即基于 T 细胞的免疫疗法施加的选择在肿瘤微环境 (TME) 中引发了补体耐药表型，在免疫编辑的肿瘤细胞中建立了 NANOG 和 CD59 之间的牢固分子联系。我们相信这些结果对 CDC 介导的治疗性抗体的临床应用具有重要意义。
