Anti-CD20 therapy acts via FcγRIIIA to diminish responsiveness of human natural killer cells

Cristina Capuano, Maddalena Romanelli, Chiara Pighi, Giuseppe Cimino, Angela Rago, Rosa Molfetta, Rossella Paolini, Angela Santoni, Ricciarda Galandrini

Research output: Contribution to journalArticlepeer-review

Abstract

Natural killer (NK) immune cells mediate antibody-dependent cellular cytotoxicity (ADCC) by aggregating FcγRIIIA/CD16, contributing significantly to the therapeutic effect of CD20 monoclonal antibodies(mAb). In this study, we show that CD16 ligationon primary human NK cells by the anti-CD20 mAb rituximab or of atumumab stably impairs the spontaneous cytotoxic response attributable to cross-tolerance of several unrelated NK-activating receptors (including NKG2D, DNAM-1, NKp46, and 2B4). Similar effects were obtained from NK cells isolated from patients with chronic lymphocytic leukemia in an autologous setting. NK cells rendered hyporesponsive in this manner were deficient in the ability of these cross-tolerized receptors to phosphorylate effector signaling molecules critical for NK cytotoxicity, including SLP-76, PLCγ2, and Vav1. These effects were associated with long-lasting recruitment of the tyrosine phosphatase SHP-1 to the CD16 receptor complex. Notably, pharmacologic inhibition of SHP-1 with sodium stibogluconate counteracted CD20 mAb-induced NK hyporesponsiveness, unveiling an unrecognized role for CD16 as a bifunctional receptor capable of engendering long-lasting NK cell inhibitory signals. Our work defines a novel mechanism of immune exhaustion induced by CD20 mAb in human NK cells, with potentially negative implications in CD20 mAb-treated patients where NK cells are partly responsible for clinical efficacy.

Original languageEnglish
Pages (from-to)4097-4108
Number of pages12
JournalCancer Research
Volume75
Issue number19
DOIs
Publication statusPublished - Oct 1 2015

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

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