CTLA-4+ Regulatory T Cells Increased in Cetuximab Treated Head and Neck Cancer Patients Suppress NK Cell Cytotoxicity and Correlate with Poor Prognosis

摘要: The EGFR-targeted antibody cetuximab is effective against head and neck cancer (HNSCC), but in only 15% to 20% of patients, the variability extent cetuximab-mediated cellular immunity not fully understood. We hypothesized that regulatory T cells (Treg) may exert a functional clinical impact on antitumor cetuximab-treated individuals. frequency, immunosuppressive phenotype, activation status Treg natural killer (NK) were analyzed circulation tumor microenvironment patients with HNSCC enrolled novel neoadjuvant, single-agent trial. Notably, treatment increased frequency CD4(+)FOXP3(+) intratumoral expressing CTLA-4, CD39, TGFβ. These suppressed antibody-dependent cytotoxicity (ADCC) their presence correlated poor outcome two prospective trial cohorts. Cetuximab expanded CTLA-4(+)FOXP3(+) vitro, part, by inducing dendritic cell maturation, combination TGFβ T-cell receptor triggering. Importantly, cetuximab-activated NK selectively eliminated preserved effector cells. In ex vivo assays, ipilimumab targeted CTLA-4(+) restored cytolytic functions mediating ADCC. Taken together, our results argue differences Treg-mediated suppression contribute response treatment, suggesting its improvement adding or other strategies ablation promote immunity.