Anti-CD20 Therapy Acts via FcγRIIIA to Diminish Responsiveness of Human Natural Killer Cells
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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 ligation on primary human NK cells by the anti-CD20 mAb rituximab or ofatumumab 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.
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FcγR engagement on NK cells by unbound tumor-specific monoclonal antibodies limits NK-cell responsiveness to stimulation.
“Fc g R engagement on NK cells by unbound tumor-specific mAbs reportedly limits NK-cell responsiveness to stimulation”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Capuano et al., 2015
FcγR engagement on NK cells by unbound tumor-specific monoclonal antibodies may represent an immunological resistance mechanism to monoclonal antibody-based targeted anticancer therapies.
“potentially identifying an immunological mechanism of resistance to targeted anticancer therapies based on mAbs”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Capuano et al., 2015
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Therapeutic options for rituximab-resistant patients
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- Authors
- Capuano, C., Romanelli, M., Pighi, C., Cimino, G., Rago, A., Molfetta, R., Paolini, R., Santoni, A., & Galandrini, R.
- Affiliations
- Sapienza University of Rome (IT)
- Istituto Pasteur (IT)
- Ospedale Santa Maria Goretti (IT)
- Corresponding author
- Galandrini, Ricciarda
- ORCID
- Venue
- Cancer Research
- Published
- 2015-09-30
- Volume
- 75
- Issue
- 19
- Pages
- 4097-4108
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2114729518
- Cited by
- 51
- References
- 47
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 3 · 2020: 7 · 2019: 5 · 2018: 9 · 2017: 5 · 2016: 5
- FWCI
- 3.11
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- anti-CD20 monoclonal antibody, rituximab, ofatumumab, natural killer cells, antibody-dependent cellular cytotoxicity, NKG2D, DNAM-1, NKp46, 2B4, SHP-1, sodium stibogluconate, SLP-76, PLCγ2, Vav1, chronic lymphocytic leukemia, immune exhaustion, receptor signaling
- MeSH terms
- Rituximab, Antibodies, Monoclonal, Antibody-Dependent Cell Cytotoxicity, Cells, Cultured, Cytoplasmic Granules, Endocytosis, Humans, Immune Tolerance, Killer Cells, Natural, Opsonin Proteins, Phosphoproteins, Phosphorylation, Protein Processing, Post-Translational, Leukemia, Lymphocytic, Chronic, B-Cell, Receptors, IgG, Cell Line, Tumor, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-vav, Phospholipase C gamma, Protein Tyrosine Phosphatase, Non-Receptor Type 6, GPI-Linked Proteins, Interferon-gamma Release Tests, Antibodies, Monoclonal, Humanized
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