2B4 (CD244) signaling by recombinant antigen-specific chimeric receptors costimulates natural killer cell activation to leukemia and neuroblastoma cells.
OBJECTIVE
Novel natural killer (NK) cell-directed strategies in cancer immunotherapy aim at specifically modulating the balance between NK cell receptor signals toward tumor-specific activation. The signaling lymphocyte activation molecule-related receptor 2B4 (CD244) is an important regulator of NK cell activation. We investigated whether 2B4-enhanced activation signals can redirect the cytolytic function of human NK cells to NK cell-resistant and autologous leukemia and tumor targets.


METHODS
In vitro-stimulated NK cells from healthy donors and pediatric leukemia patients were gene modified with CD19 or G(D2)-specific chimeric receptors containing either the T-cell receptor zeta or 2B4 endodomain alone or combined.


RESULTS
Chimeric 2B4 signaling alone failed to induce interleukin-2 receptor up-regulation and cytokine secretion but triggered a specific degranulation response. Integration of the 2B4 endodomain into T-cell receptor zeta chimeric receptors significantly enhanced all aspects of the NK cell activation response to antigen-expressing leukemia or neuroblastoma cells, including CD25 up-regulation, secretion of IFN-gamma and tumor necrosis factor-alpha, release of cytolytic granules, and growth inhibition, and overcame NK cell resistance of autologous leukemia cells while maintaining antigen specificity.


CONCLUSIONS
These data indicate that the 2B4 receptor has a potent costimulatory effect in NK cells. Antigen-specific 2B4zeta-expressing NK cells may be a powerful new tool for adoptive immunotherapy of leukemia and other malignancies.
Altvater
Bianca
B
Department of Pediatric Hematology and Oncology, University Children's Hospital Muenster, Muenster, Germany.
Landmeier
Silke
S
Pscherer
Sibylle
S
Temme
Jaane
J
Schweer
Katharina
K
Kailayangiri
Sareetha
S
Campana
Dario
D
Juergens
Heribert
H
Pule
Martin
M
Rossig
Claudia
C
D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19 / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D007938:Leukemia / Q000276:immunology / Q000628:therapy; D008213:Lymphocyte Activation / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology / Q000378:metabolism; D018302:Neoplasms, Neuroepithelial / Q000276:immunology / Q000628:therapy; D009447:Neuroblastoma / Q000276:immunology / Q000628:therapy; D015202:Protein Engineering; D011946:Receptors, Antigen / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family
D015703:Antigens, CD; D018941:Antigens, CD19; C084093:CD244 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; D011946:Receptors, Antigen; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D000071176:Signaling Lymphocytic Activation Molecule Family