期刊
BLOOD
卷 123, 期 5, 页码 678-686出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2013-08-519199
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资金
- National Institutes of Health [CA34233, CA33399]
- Leukemia and Lymphoma Society
- American Society of Hematology
- American Society of Clinical Oncology
- Damon Runyon Foundation
- European Research Council (THINK Advanced Grant)
- Institut National de la Sante et de la Recherche Medicale
- Centre national de la recherche scientifique
- Aix Marseille University (Centre d'Immunologie de Marseille-Luminy)
Natural killer (NK) cells mediate antilymphoma activity by spontaneous cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) when triggered by rituximab, an anti-CD20 monoclonal antibody (mAb) used to treat patients with B-cell lymphomas. The balance of inhibitory and activating signals determines the magnitude of the efficacy of NK cells by spontaneous cytotoxicity. Here, using a killer-cell immunoglobulin-like receptor (KIR) transgenic murine model, we show that blockade of the interface of inhibitory KIRs with major histocompatibility complex (MHC) class I antigens on lymphoma cells by anti-KIR antibodies prevents a tolerogenic interaction and augments NK-cell spontaneous cytotoxicity. In combination with anti-CD20 mAbs, anti-KIR treatment induces enhanced NK-cell-mediated, rituximab-dependent cytotoxicity against lymphoma in vitro and in vivo in KIR transgenic and syngeneic murine lymphoma models. These results support a therapeutic strategy of combination rituximab and KIR blockade through lirilumab, illustrating the potential efficacy of combining a tumor-targeting therapy with an NK-cell agonist, thus stimulating the postrituximab antilymphoma immune response.
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