RT Journal Article SR Electronic T1 PD-L1 Mediates Dysfunction in Activated PD-1+ NK Cells in Head and Neck Cancer Patients JF Cancer Immunology Research JO Cancer Immunol Res FD American Association for Cancer Research SP 1548 OP 1560 DO 10.1158/2326-6066.CIR-18-0062 VO 6 IS 12 A1 Concha-Benavente, Fernando A1 Kansy, Benjamin A1 Moskovitz, Jessica A1 Moy, Jennifer A1 Chandran, Uma A1 Ferris, Robert L. YR 2018 UL http://cancerimmunolres.aacrjournals.org/content/6/12/1548.abstract AB Inhibitory immune-checkpoint receptors (ICRs), including programmed death 1 (PD-1), have been characterized as exhaustion markers on T cells that infiltrate the tumor microenvironment (TME) of many cancer types, including head and neck cancer (HNC). However, expression and function of ICRs, including PD-1, on natural killer (NK) cells remains less defined. NK cells are innate immune effector cells that lyse epidermal growth factor receptor–overexpressing HNC cells via cetuximab-mediated antibody-dependent cytotoxicity. Cetuximab is clinically effective but only in 10% to 15% of patients. Therefore, it is necessary to investigate how immunomodulation with cetuximab or PD-1 blockade might enhance NK cell responses in the TME and improve monoclonal antibody therapeutic efficacy. We observed that expression of PD-1 on NK cells marks an activated phenotype, which was suppressed only after binding programmed death ligand-1 (PD-L1). HNC patients who exhibit higher circulating PD-1+ NK cells associate with better clinical outcome, and these cells are enriched in the TME. Cetuximab-mediated NK cell activation increased PD-1 expression on NK cells in vitro, which was confirmed in vivo in a prospective neoadjuvant cetuximab trial. In contrast, PD-L1 ligation of PD-1+ NK cells diminished their activation status, whereas PD-1 blockade increased cetuximab-mediated NK cell activation and cytotoxicity, but only against HNC targets with high PD-L1 expression. Therefore, blocking the PD-1–PD-L1 axis may be a useful strategy to reverse immune evasion of HNC tumors with high PD-L1 expression during cetuximab therapy by reversing NK cell dysfunction.