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FcRIIIa Expression Is Not Increased on Natural Killer Cells Expressing the FcRIIIa-158V Allotype

¹ EA3853 "Immuno-Pharmaco-Genetique des Anticorps thérapeutiques," Université François Rabelais de Tours; ² Laboratoire d'Immunologie, CHRU de Tours, Tours, France; and ³ Université d'Auvergne-Clermont 1, Clermont-Ferrand, France

Requests for reprints: Gilles Thibault, EA3853 "Immuno-Pharmaco-Genetique des Anticorps therapeutiques," Laboratoire d'Immunologie, Faculte de Medecine, 10 Boulevard Tonnelle, 37032 Tours Cedex, France. Phone: 33-2-4747-4747, ext. 71823; Fax: 33-2-3438-9412; E-mail: thibault{at}med.univ-tours.fr.

Key Words: FcRIIIa/CD16a • natural killer cells • rituximab • FCGR3A polymorphism • Flow cytometry

The presence of a valine (V) versus a phenylanaline (F) at position 158 of FcRIIIa/CD16a improves the affinity for IgG and is associated with higher therapeutic response to rituximab. Increased CD16 expression on natural killer (NK) cells from donors with the VV or VF versus FF genotype has recently been reported. We indeed observed higher binding of the anti-CD16 monoclonal antibody (mAb) 3G8 on NK cells from V carriers (VV = VF > FF). However, the binding of two other anti-CD16 mAbs, LNK16 and DJ130c, decreased with the number of V allele (VV < VF < FF). CD16 transcript levels were independent on the genotype. Rituximab binding to NK cells from V carriers was higher than its binding to FF NK cells at low concentrations (10 and 100 µg/mL). However, the difference was nearly completely abolished at saturating concentrations (1,000 µg/mL). Finally, nearly 100% of CD16-expressing NK cells displayed a complete down-modulation of the receptor after optimal engagement by plate-bound 3G8, whatever the genotype. By contrast, the percentages of NK cells down-modulating CD16 after competitive engagement of the receptor by plate-bound rituximab increased with the number of V allele (FF, 18.2 ± 8.6%; VF, 32.0 ± 4.9%; and VV, 42.4 ± 9.9%). These results are in discrepancy with the expected increased competition that would result from an increased expression of CD16 on VV and VF NK cells. We conclude that increased binding and functional and clinical responses associated with the high-affinity FcRIIIa-158V are unrelated to an increased expression of this allotype. [Cancer Res 2008;68(4):976–80]