In vivo tumor cell rejection induced by NK cell inhibitory receptor blockade: Maintained tolerance to normal cells even in the presence of IL‐2
Open Access
- 3 March 2010
- journal article
- research article
- Published by Wiley in European Journal of Immunology
- Vol. 40 (3), 813-823
- https://doi.org/10.1002/eji.200939755
Abstract
Missing-self-reactivity can be mimicked by blocking self-specific inhibitory receptors on NK cells, leading to increased rejection of syngeneic tumor cells. Using a mouse model, we investigated whether Ab-mediated blocking of inhibitory receptors, to a degree where NK cells rejected syngeneic tumor cells, would still allow self-tolerance toward normal syngeneic cells. Ly49C/I inhibitory receptors on C57BL/6 (H-2b) NK cells were blocked with F(ab')2 fragments of the mAb 5E6. Inhibitory receptor blockade in vivo caused rejection of i.v. inoculated fluorescence-labeled syngeneic lymphoma line cells but not of syngeneic spleen cells, BM cells or lymphoblasts. The selective rejection of tumor cells was NK cell-dependent and specifically induced by Ly49C/I blockade. Moreover, selective tumor rejection was maintained after treatment with 5E6 F(ab')2 for 9 wk, arguing against the induction of NK cell anergy or autoreactivity during this time. Combination therapy using 5E6 F(ab')2 together with high dose IL-2 treatment further increased lymphoma cell rejection. In addition, combination therapy reduced growth of melanoma cell line tumors established by s.c. inoculation 3 days before start of treatment. Our results demonstrate that inhibitory receptor blockade does not result in attack on normal cells, despite potent reactivity against MHC class I-expressing tumors.Keywords
This publication has 49 references indexed in Scilit:
- Preclinical characterization of 1-7F9, a novel human anti–KIR receptor therapeutic antibody that augments natural killer–mediated killing of tumor cellsBlood, 2009
- Genetic and antibody-mediated reprogramming of natural killer cell missing-self recognition in vivoProceedings of the National Academy of Sciences, 2009
- Natural Killer Cells in Allogeneic Transplantation: Effect on Engraftment, Graft- versus-Tumor, and Graft-versus-Host ResponsesTransplantation and Cellular Therapy, 2009
- Reduction of GVHD and enhanced antitumor effects after adoptive infusion of alloreactive Ly49-mismatched NK cells from MHC-matched donorsBlood, 2006
- The relevance of natural killer cell human leucocyte antigen epitopes and killer cell immunoglobulin-like receptors in bone marrow transplantationVox Sanguinis, 2006
- NATURAL KILLER CELLS IN ANTIVIRAL DEFENSE: Function and Regulation by Innate CytokinesAnnual Review of Immunology, 1999
- Host MHC class I gene control of NK‐cell specificity in the mouseImmunological Reviews, 1997
- Allorecognition by murine natural killer cells: lysis of T-lymphoblasts and rejection of bone-marrow graftsImmunological Reviews, 1997
- The Role of Ly49A and 5E6(Ly49C) Molecules in Hybrid Resistance Mediated by Murine Natural Killer Cells Against Normal T Cell BlastsImmunity, 1996
- In search of the ‘missing self’: MHC molecules and NK cell recognitionImmunology Today, 1990