Low number of KIR ligands in lymphoma patients favors a good rituximab-dependent NK cell response. (1st January 2021)

• Record Type: Journal Article
• Authors: Makanga, Dhon Roméo; Jullien, Maxime; David, Gaëlle; Legrand, Nolwenn; Willem, Catherine; Dubreuil, Léa; Walencik, Alexandre; Touzeau, Cyrille; Gastinne, Thomas; Tessoulin, Benoit; Le Gouill, Steven; Mahé, Béatrice; Gagne, Katia; Chevallier, Patrice; Clemenceau, Béatrice; Retière, Christelle
• Is Part Of: Oncoimmunology. Volume 10:Number 1(2021)
• Publication Date: 2021-01-01
• Subjects: KIR -- hla -- adcc -- rituximab -- nk cells -- cd16 -- non hodgkin lymphoma; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2021.1936392
• Languages: English
• ISSNs: 2162-402X

Abstract

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.