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

Robert Godal, Veronika Bachanova, Michelle Gleason, Valarie McCullar, Gong H. Yun, Sarah Cooley, Michael R. Verneris, Philip B. McGlave, Jeffrey S. Miller

Research output: Contribution to journalArticlepeer-review

79 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)612-621
Number of pages10
JournalBiology of Blood and Marrow Transplantation
Volume16
Issue number5
DOIs
StatePublished - May 2010

Bibliographical note

Funding Information:
Financial disclosure: This work was supported in part by National Institutes of Health Grants P01-CA-65493 (to J.S.M., S.C., and P.B.M.), and P01-CA-111412 (to J.S.M., S.C., and M.R.V.).

Keywords

  • Immunotherapy
  • Leukemia
  • NK cells

Fingerprint

Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this