Natural killer cell killing of acute myelogenous leukemia and acute lymphoblastic leukemia blasts by killer cell immunoglobulin-like receptor-negative natural killer cells after NKG2A and LIR-1 blockade.
Although the study of natural killer (NK) cell alloreactivity has been dominated by studies of killer cell immunoglobulin-like receptors (KIRs), we hypothesized that NKG2A and LIR-1, present on 53% +/- 13% and 36% +/- 18% of normal NK cells, respectively, play roles in the NK cell killing of primary leukemia targets. KIR(-) cells, which compose nearly half of the circulating NK cell population, exhibit tolerance to primary leukemia targets, suggesting signaling through other inhibitory receptors. Both acute myelogenous leukemia and acute lymphoblastic leukemia targets were rendered susceptible to lysis by fresh resting KIR(-) NK cells when inhibitory receptor-major histocompatibility class I interactions were blocked by pan-HLA antibodies, demonstrating that these cells are functionally competent. Blockade of a single inhibitory receptor resulted in slightly increased killing, whereas combined LIR-1 and NKG2A blockade consistently resulted in increased NK cell cytotoxicity. Dual blockade of NKG2A and LIR-1 led to significant killing of targets by resting KIR(-) NK cells, demonstrating that this population is not hyporesponsive. Together these results suggest that alloreactivity of a significant fraction of KIR(-) NK cells is mediated by NKG2A and LIR-1. Thus strategies to interrupt NKG2A and LIR-1 in combination with anti-KIR blockade hold promise for exploiting NK cell therapy in acute leukemias.
Division of Adult Hematology, Oncology and Transplantation, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, Minnesota, USA.
Robert
R
Godal
Veronika
V
Bachanova
Michelle
M
Gleason
Valarie
V
McCullar
Gong H
GH
Yun
Sarah
S
Cooley
Michael R
MR
Verneris
Philip B
PB
McGlave
Jeffrey S
JS
Miller
D000906:Antibodies / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology*; D001752:Blast Crisis / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015395:Histocompatibility Antigens Class I; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D015470:Leukemia, Myeloid, Acute / Q000276:immunology* / Q000473:pathology; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D055654:NK Cell Lectin-Like Receptor Subfamily C / Q000037:antagonists & inhibitors / Q000276:immunology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology* / Q000473:pathology; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology*; D054340:Receptors, KIR
D000906:Antibodies; D015703:Antigens, CD; D015395:Histocompatibility Antigens Class I; C527054:KLRC1 protein, human; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D055654:NK Cell Lectin-Like Receptor Subfamily C; D011971:Receptors, Immunologic; D054340:Receptors, KIR