IL-2-activated haploidentical NK cells restore NKG2D-mediated NK-cell cytotoxicity in neuroblastoma patients by scavenging of plasma MICA.
NK group 2D (NKG2D)-expressing NK cells exhibit cytolytic activity against various tumors after recognition of the cellular ligand MHC class I chain-related gene A (MICA). However, release of soluble MICA (sMICA) compromises NKG2D-dependent NK-cell cytotoxicity leading to tumor escape from immunosurveillance. Although some molecular details of the NKG2D-MICA interaction have been elucidated, its impact for donor NK (dNK) cell-based therapy of solid tumors has not been studied. Within an ongoing phase I/II trial, we used allogeneic IL-2 activated dNK cells after haploidentical stem cell transplantation for immunotherapy of patients with high-risk stage IV neuroblastoma. NKG2D levels on activated dNK cells increased strongly when compared with freshly isolated dNK cells and correlated with enhanced NK-cell cytotoxicity. Most importantly, elevated sMICA levels in patients plasma correlated significantly with impaired dNK-cell-mediated cytotoxicity. This effect could be reversed by high-dose infusion of activated dNK cells, which display high levels of surface NKG2D. Our data suggest that the provided excess of NKG2D leads to clearance of sMICA and preserves cytotoxicity of dNK cells via non-occupied NKG2D. In conclusion, our results identify this tumor immune escape mechanism as a target to improve immunotherapy of neuroblastoma and presumably other tumors.
Pediatric Hematology and Oncology Laboratory for Stem Cell Transplantation and Immunotherapy, Hospital of Johann Wolfgang Goethe-University, Frankfurt, Germany. stephan.kloess@kgu.de
Stephan
S
Kloess
Sabine
S
Huenecke
Daniel
D
Piechulek
Ruth
R
Esser
Joachim
J
Koch
Claudia
C
Brehm
Jan
J
Soerensen
Tanja
T
Gardlowski
Andrea
A
Brinkmann
Peter
P
Bader
Jakob
J
Passweg
Thomas
T
Klingebiel
Dirk
D
Schwabe
Ulrike
U
Koehl
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology* / Q000378:metabolism; D019520:Living Donors; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D015166:Monitoring, Immunologic; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000276:immunology* / Q000378:metabolism; D009367:Neoplasm Staging; D009447:Neuroblastoma / Q000097:blood / Q000276:immunology* / Q000628:therapy; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous; D019139:Tumor Escape / Q000276:immunology
D015395:Histocompatibility Antigens Class I; C508594:IL2 protein, human; D007376:Interleukin-2; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; D055655:NK Cell Lectin-Like Receptor Subfamily K