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Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response

Abstract : The antibody-dependent cellular cytotoxicity (ADCC) effector function of natural killer (NK) cells is one of the known mechanisms of action for rituximab-based anti-cancer immunotherapy. Inhibition of the ADCC function of NK cells through interactions between inhibitory killer cell immunoglobulin-like receptors (KIRs) and HLA class I ligands is associated with resistance of cancers to rituximab. In this study, we deeply investigated the impact of KIR, HLA class I, and CD16 genotypes on rituximab-dependent NK cell responses in both an in vitro cellular model from healthy blood donors and ex vivo rituximab-treated non-Hodgkin lymphoma (NHL) patients. We highlight that an HLA environment with limited KIR ligands is beneficial to promoting a higher frequency of KIR+ NK cells including both educated and uneducated NK cells, two NK cell compartments that demonstrate higher rituximab-dependent degranulation than KIR- NK cells. In contrast, a substantial KIR ligand environment favors a higher frequency of poorly effective KIR- NK cells and numerous functional KIR/HLA inhibitions of educated KIR+ NK cells. These phenomena explain why NHL patients with limited KIR ligands respond better to rituximab. In this HLA environment, CD16 polymorphism appears to have a collateral effect. Furthermore, we show the synergic effect of KIR2DS1, which strongly potentiates NK cell ADCC from C2- blood donors against C2+ target cells. Taken together, these results pave the way for stronger prediction of rituximab responses for NHL patients. HLA class I typing and peripheral blood KIR+ NK cell frequency could be simple and useful markers for predicting rituximab response.
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https://www.hal.inserm.fr/inserm-03287975
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Submitted on : Friday, July 16, 2021 - 9:20:28 AM
Last modification on : Wednesday, October 20, 2021 - 3:19:34 AM
Long-term archiving on: : Sunday, October 17, 2021 - 6:12:16 PM

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Dhon Makanga, Maxime Jullien, Gaëlle David, Nolwenn Legrand, Catherine Willem, et al.. Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response. OncoImmunology, Taylor & Francis, 2021, 10 (1), pp.1936392. ⟨10.1080/2162402x.2021.1936392⟩. ⟨inserm-03287975⟩

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