NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59
Sung Wook Son, Eunho Cho, Hanbyoul Cho, Seon Rang Woo, Hyo-Jung Lee, Se Jin Oh, Suyeon Kim, Jae‐Hoon Kim, Eun Joo Chung, Joon‐Yong Chung, Min Kim, Kwon‐Ho Song, Tae Woo Kim
Abstract
Abstract 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.