Contributions
Abstract: PB1543
Type: Publication Only
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
NK cells are educated to stay responsive to cells with diminished HLA class I expression as a consequence of viral- or tumor-transformation. Inhibitory KIR and NKG2A receptors are known to educate human NK cells upon interaction with cells expressing their cognate HLA class I ligands.
Aims
To addressed if the inhibitory receptor LIR-1 (LILRB1/ILT2/CD85j) that is widely expressed on human NK cells and mediates inhibition via similar mechanisms as KIR and NKG2A, can mediate education and contribute to anti-tumor functions of NK cells.
Methods
NK cells were obtained from healthy donors and used resting, cytokine-activated or following ex vivo expansion. NK cell phenotype and activation were addressed using flow cytometry, while tumor cytotoxicity was assessed using 51Cr-release assays with flow cytometry cell sorted NK cell subsets. Antibody-dependent cellular cytotoxicity was asses using the monoclonal antibody rituximab.
Results
LIR-1 can mediate NK cell education. This novel finding was exclusive to expanded NK cells and associated with high expression of granzyme B and DNAM-1, which both have been linked to NK cell education. Corroborating the rheostat education model, LIR-1 co-expression with an educating KIR further increased the responsiveness of expanded NK cells. Inversely, antibody masking of LIR-1 decreased the responsiveness. Using rituximab and a panel of CD20+ target cells, LIR-1+ expanded NK cells displayed high intrinsic ADCC that, in contrast to KIR and NKG2A, was not inhibited by HLA class I.
Conclusion
Overall, these findings define a unique NK cell subset attractive for adoptive cell therapy to treat cancer. Given that LIR-1 binds most HLA class I molecules, this subset may be utilized in both autologous and allogeneic settings to innately reject HLA class I- tumor cells as well as HLA class I+ target cells when combined with anti-tumor antibodies. Further studies are warranted to explore the potential of this subset in clinical therapy.
Keyword(s): ADCC, Adoptive immunotherapy, Natural killer, Rituximab
Abstract: PB1543
Type: Publication Only
Session title: Gene therapy, cellular immunotherapy and vaccination - Biology & Translational Research
Background
NK cells are educated to stay responsive to cells with diminished HLA class I expression as a consequence of viral- or tumor-transformation. Inhibitory KIR and NKG2A receptors are known to educate human NK cells upon interaction with cells expressing their cognate HLA class I ligands.
Aims
To addressed if the inhibitory receptor LIR-1 (LILRB1/ILT2/CD85j) that is widely expressed on human NK cells and mediates inhibition via similar mechanisms as KIR and NKG2A, can mediate education and contribute to anti-tumor functions of NK cells.
Methods
NK cells were obtained from healthy donors and used resting, cytokine-activated or following ex vivo expansion. NK cell phenotype and activation were addressed using flow cytometry, while tumor cytotoxicity was assessed using 51Cr-release assays with flow cytometry cell sorted NK cell subsets. Antibody-dependent cellular cytotoxicity was asses using the monoclonal antibody rituximab.
Results
LIR-1 can mediate NK cell education. This novel finding was exclusive to expanded NK cells and associated with high expression of granzyme B and DNAM-1, which both have been linked to NK cell education. Corroborating the rheostat education model, LIR-1 co-expression with an educating KIR further increased the responsiveness of expanded NK cells. Inversely, antibody masking of LIR-1 decreased the responsiveness. Using rituximab and a panel of CD20+ target cells, LIR-1+ expanded NK cells displayed high intrinsic ADCC that, in contrast to KIR and NKG2A, was not inhibited by HLA class I.
Conclusion
Overall, these findings define a unique NK cell subset attractive for adoptive cell therapy to treat cancer. Given that LIR-1 binds most HLA class I molecules, this subset may be utilized in both autologous and allogeneic settings to innately reject HLA class I- tumor cells as well as HLA class I+ target cells when combined with anti-tumor antibodies. Further studies are warranted to explore the potential of this subset in clinical therapy.
Keyword(s): ADCC, Adoptive immunotherapy, Natural killer, Rituximab