Silencing EGFR-upregulated Expression of CD55 and CD59 Activates the Complement System and Sensitizes Lung Cancer to Checkpoint Blockade

The complement system is a critical immune component, yet its role in tumor immune evasion and CD8 T cell activation is not clearly defined. Here, we demonstrate that epidermal growth factor receptor (EGFR)/Wnt signaling induces β-catenin-mediated long noncoding RNA (lncRNA) LINC00973 expression to sponge CD55-targeting miR-216b and CD59-targeting miR-150. The consequently upregulated CD55/CD59 expression suppresses the complement system and cytokine secretion required for CD8 T cell activation. CD55/CD59-neutralizing antibody treatment or mutation of the LINC00973 promoter activates the complement and CD8 T cells, inhibiting tumor growth. Importantly, combined anti-CD55/CD59 and anti-programmed death 1 (anti-PD-1) antibody treatments elicit a synergistic tumor-inhibiting effect. In addition, CD55/CD59 levels are inversely correlated with infiltration of M1 macrophages and CD8 T cells in human lung cancer specimens and predict patient outcome. These findings underscore the critical role of EGFR/Wnt/β-catenin-upregulated CD55/CD59 expression in inhibiting the complement and CD8 T cell activation for tumor immune evasion and immune checkpoint blockade resistance and identify a potential combination therapy to overcome these effects.