Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC

Atsushi Inagaki; Takashi Ishida; Hiroki Yano; Toshihiko Ishii; Shigeru Kusumoto; Asahi Ito; Masaki Ri; Fumiko Mori; Jianmin Ding; Hirokazu Komatsu; Shinsuke Iida; Ryuzo Ueda

doi:10.1002/ijc.24351

Expression of the ULBP ligands for NKG2D by B-NHL cells plays an important role in determining their susceptibility to rituximab-induced ADCC

Int J Cancer. 2009 Jul 1;125(1):212-21. doi: 10.1002/ijc.24351.

Authors

Atsushi Inagaki¹, Takashi Ishida, Hiroki Yano, Toshihiko Ishii, Shigeru Kusumoto, Asahi Ito, Masaki Ri, Fumiko Mori, Jianmin Ding, Hirokazu Komatsu, Shinsuke Iida, Ryuzo Ueda

Affiliation

¹ Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan.

PMID: 19358282
DOI: 10.1002/ijc.24351

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) is a major antitumor mechanism of action of therapeutic monoclonal antibodies (mAbs). The aim of this study was to identify tumor-associated factors which determine susceptibility to rituximab-induced ADCC. Thirty different CD20+ non-Hodgkin lymphoma cell lines were phenotyped for characteristics such as level of expression of NKG2D ligands, and the influence thereof on susceptibility to rituximab-induced ADCC was established. The present study demonstrated that tumor cell susceptibility to rituximab-induced ADCC was determined by 3 major tumor-associated factors: (i) the amount of the target molecule, CD20; (ii) the amount of the ligands for inhibitory killer Ig-like receptors, major histocompatibility complex class I; and (iii) the amounts of some of the NKG2D ligands, especially UL16-binding protein (ULBP) 1-3. The importance of the ULBPs was confirmed using antibody blockade. In conclusion, this is the first report to show the importance for rituximab-induced ADCC of ULBPs expressed on tumor cells. The ULBPs could be valuable diagnostic biological markers and significant targets for immunotherapy to improve efficacy not only of rituximab but also of other therapeutic mAbs.

Publication types

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

MeSH terms

Antibodies, Monoclonal / pharmacology*
Antibodies, Monoclonal, Murine-Derived
Antibody-Dependent Cell Cytotoxicity / drug effects*
Antibody-Dependent Cell Cytotoxicity / immunology
Antigens, CD20 / immunology
Antineoplastic Agents / pharmacology*
Cathepsin B / metabolism
Flow Cytometry
GPI-Linked Proteins
HLA Antigens / metabolism
HLA-G Antigens
Histocompatibility Antigens Class I / metabolism
Humans
Intercellular Signaling Peptides and Proteins / chemistry
Intercellular Signaling Peptides and Proteins / immunology
Intercellular Signaling Peptides and Proteins / metabolism*
Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins / immunology
Intracellular Signaling Peptides and Proteins / metabolism*
Killer Cells, Natural / immunology
Killer Cells, Natural / metabolism
Lymphoma, Non-Hodgkin / drug therapy
Lymphoma, Non-Hodgkin / metabolism*
Lymphoma, Non-Hodgkin / pathology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / immunology
Membrane Proteins / metabolism*
NK Cell Lectin-Like Receptor Subfamily K / genetics
NK Cell Lectin-Like Receptor Subfamily K / metabolism*
Rituximab
Tumor Cells, Cultured

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Murine-Derived
Antigens, CD20
Antineoplastic Agents
GPI-Linked Proteins
HLA Antigens
HLA-G Antigens
Histocompatibility Antigens Class I
Intercellular Signaling Peptides and Proteins
Intracellular Signaling Peptides and Proteins
KLRK1 protein, human
Membrane Proteins
NK Cell Lectin-Like Receptor Subfamily K
ULBP1 protein, human
ULBP3 protein, human
Rituximab
Cathepsin B