NANOG confers resistance to complement-dependent cytotoxicity in immune-edited tumor cells through up-regulating CD59

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.

Membrane-Bound Complement Regulatory Proteins in Breast Cancer: Are They Best Therapeutic Targets?

“…Other studies have reported that enrichment of CSCs in the tumor population can confer resistance to therapy, providing worse scenarios for the prognosis of Membrane-Bound Complement Regulatory Proteins in Breast Cancer: Are they Best Therapeutic… DOI: http://dx.doi.org/10.5772/intechopen.109945 patients. In tumor cells (CaSki, H1299, HCT116, and HEK293), NANOG increased CD59 expression, contributing to the resistance of tumor cells against complementdependent cytotoxicity (CDC) [79]. Another example is the role of CD55 in the maintenance of CSCs by regulating self-renewal and cisplatin resistance.…”

Novel Roles of Nanog in Cancer Cells and Their Extracellular Vesicles

“…In a NANOG -overexpressing cell line (CaSki- NANOG ), CD59 was up-regulated, and the resistance to CDC increased. NANOG directly bound to the CD59 promoter to enhance its expression activity [ 8 ].…”