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Abstract
Adoptive transfer of allogeneic natural killer (NK) cells is becoming a credible immunotherapy for hematological malignancies. In the present work, using an optimized expansion/activation protocol of human NK cells, we generate expanded NK cells (eNK) with increased expression of CD56 and NKp44, while maintaining that of CD16. These eNK cells exerted significant cytotoxicity against cells from 34 B-CLL patients, with only 1 sample exhibiting resistance. This sporadic resistance did not correlate with match between KIR ligands expressed by the eNK cells and the leukemic cells, while cells with match resulted sensitive to eNK cells. This suggests that KIR mismatch is not relevant when expanded NK cells are used as effectors. In addition, we found two examples of de novo resistance to eNK cell cytotoxicity during the clinical course of the disease. Resistance correlated with KIR-ligand match in one of the patients, but not in the other, and was associated with a significant increase in PD-L1 expression in the cells from both patients. Treatment of one of these patients with idelalisib correlated with the loss of PD-L1 expression and with re-sensitization to eNK cytotoxicity. We confirmed the idelalisib-induced decrease in PD-L1 expression in the B-CLL cell line Mec1 and in cultured cells from B-CLL patients. As a main conclusion, our results reinforce the feasibility of using expanded and activated allogeneic NK cells in the treatment of B-CLL.
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Details
1 University of Zaragoza and Aragón Health Research Institute (IIS Aragón), Apoptosis, Immunity & Cancer Group, Zaragoza, Spain (GRID:grid.11205.37) (ISNI:0000 0001 2152 8769)
2 Immunogenetics-HLA Laboratory, Puerta de Hierro Hospital, Majadahonda, Madrid, Spain (GRID:grid.73221.35) (ISNI:0000 0004 1767 8416)
3 Lozano Blesa Hospital, Hematology Department, Zaragoza, Spain (GRID:grid.11205.37)
4 Miguel Servet Hospital, Hematology Department, Zaragoza, Spain (GRID:grid.411106.3) (ISNI:0000 0000 9854 2756)
5 Lozano Blesa Hospital, Hematology Department, Zaragoza, Spain (GRID:grid.411106.3)
6 IRMB, Univ Montpellier, INSERM, CNRS, Montpellier, France (GRID:grid.121334.6) (ISNI:0000 0001 2097 0141); IRMB, CHU Montpellier, Montpellier, France (GRID:grid.462469.b)
7 University of Zaragoza and Aragón Health Research Institute (IIS Aragón), Apoptosis, Immunity & Cancer Group, Zaragoza, Spain (GRID:grid.11205.37) (ISNI:0000 0001 2152 8769); University of Zaragoza and Aragón Health Research Institute (IIS Aragón), Apoptosis, Immunity & Cancer Group, Department Biochemistry and Molecular and Cell Biology, Faculty of Sciences, Zaragoza, Spain (GRID:grid.11205.37) (ISNI:0000 0001 2152 8769)