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

Dhon Roméo Makanga; Maxime Jullien; Gaëlle David; Nolwenn Legrand; Catherine Willem; Léa Dubreuil; Alexandre Walencik; Cyrille Touzeau; Thomas Gastinne; Benoit Tessoulin; Steven Le Gouill; Béatrice Mahé; Katia Gagne; Patrice Chevallier; Béatrice Clemenceau; Christelle Retière

doi:10.1080/2162402X.2021.1936392

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

Oncoimmunology. 2021 Jun 14;10(1):1936392. doi: 10.1080/2162402X.2021.1936392.

Authors

Dhon Roméo Makanga^{1

2

3}, Maxime Jullien⁴, Gaëlle David^{1

2

3}, Nolwenn Legrand^{1

2

3}, Catherine Willem^{1

2

3}, Léa Dubreuil^{1

2

3}, Alexandre Walencik¹, Cyrille Touzeau⁴, Thomas Gastinne⁴, Benoit Tessoulin⁴, Steven Le Gouill⁴, Béatrice Mahé⁴, Katia Gagne^{1

2

3

5}, Patrice Chevallier^{2

3

4}, Béatrice Clemenceau^{2

3}, Christelle Retière^{1

2

3}

Affiliations

¹ Etablissement Français Du Sang, Nantes, Nantes, France.
² Université De Nantes, INSERM U1232 CNRS, CRCINA, Nantes, France.
³ LabEx IGO "Immunotherapy, Graft, Oncology", Nantes, France.
⁴ Hematology Clinic, CHU, Nantes, France.
⁵ LabEx Transplantex, Université De Strasbourg, Strasbourg, France.

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.

Keywords: KIR; adcc; cd16; hla; nk cells; non hodgkin lymphoma; rituximab.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antibody-Dependent Cell Cytotoxicity
Humans
Killer Cells, Natural*
Ligands
Lymphoma*
Receptors, KIR*
Rituximab* / pharmacology

Substances

Ligands
Receptors, KIR
Rituximab

Grants and funding

This work was financially supported by the Etablissement Français du Sang (EFS)/Centre Pays de la Loire and by grants from la Ligue contre le Cancer (comité de Loire-Atlantique et comité de Charente Maritime), Leucémie Espoir Atlantique Famille (LEAF) and l’Agence de Biomédecine (ABM). DRM is a PhD student supported by Industrial Agreement for Training Through Research Grants 2017/0850. LD is a PhD student supported by la Région Pays de la Loire/EFS Centre Pays de la Loire (N°2018-09766);Région Centre Pays de la Loire/EFS [N°2018-09766];ANRT [2017/0850];