Natural killer: dendritic cell activation using anti-CD137 mAb improves cetuximab mediated innate and adaptive immune responses in head and neck cancer (TUM7P.948)

Abstract

Abstract EGFR-specific mAb cetuximab mediated activation of NK by FcγRIIIa cross-linking is important for anti-tumor immunity.Following cetuximab activation,NK express costimulatory receptor CD137, which can be ligated to improve activity of cetuximab-activated NK,which promote DC maturation and CD8+ T-cell priming, leading to tumor antigen spreading and Th1 cytokine release through NK-DC cross-talk. We show that the clinically available CD137 agonist mAb augments cetuximab-mediated ADCC in FcγRIIIa-V/F donors,but not in poor binding FcγRIIIa-F/F.We show that cetuximab-activated NK induce CD137 expression on DC, which can be further stimulated by CD137 mAb, leading to enhanced DC maturation and cross-presentation capacity.In a prospective phase II trial of neoadjuvant cetuximab in stage III/IV HNC patients, intratumoral activated NK cells also upregulated CD137, which was influenced by FcγRIIIa-V/F polymorphism. Moreover, cetuximab treatment induces CD137 expression on intratumoral activated CTL.We show that FcγRIIIaV/F polymorphism on NK cells greatly influences their induction of CD137 expression, as does the EGFR receptor density on HNC.Thus, careful selection of HNC patients in combination immunotherapy using cetuximab plus CD137 mAb may be necessary, using EGFR level of expression and FcgammaRIIIa genotype, to optimize NK:DC priming of tumor antigen specific CTL.Results suggest a beneficial effect of combination of cetuximab and CD137 mAb in currently designed clinical trials.