Activated Allogeneic NK Cells Preferentially Kill Poor Prognosis B-Cell Chronic Lymphocytic Leukemia Cells.
Mutational status ofTP53together with expression of wild-type (wt)IGHVrepresents the most widely accepted biomarkers, establishing a very poor prognosis in B-cell chronic lymphocytic leukemia (B-CLL) patients. Adoptive cell therapy using allogeneic HLA-mismatched Natural killer (NK) cells has emerged as an effective and safe alternative in the treatment of acute myeloid and lymphoid leukemias that do not respond to traditional therapies. We have described that allogeneic activated NK cells eliminate hematological cancer cell lines with multidrug resistance acquired by mutations in the apoptotic machinery. This effect depends on the activation protocol, being B-lymphoblastoid cell lines (LCLs) the most effective stimulus to activate NK cells. Here, we have further analyzed the molecular determinants involved in allogeneic NK cell recognition and elimination of B-CLL cells, including the expression of ligands of the main NK cell-activating receptors (NKG2D and NCRs) and HLA mismatch. We present preliminary data suggesting that B-CLL susceptibility significantly correlates with HLA mismatch between NK cell donor and B-CLL patient. Moreover, we show that the sensitivity of B-CLL cells to NK cells depends on the prognosis based onTP53andIGHVmutational status. Cells from patients with worse prognosis (mutatedTP53and wtIGHV) are the most susceptible to activated NK cells. Hence, B-CLL prognosis may predict the efficacy of allogenic activated NK cells, and, thus, NK cell transfer represents a good alternative to treat poor prognosis B-CLL patients who present a very short life expectancy due to lack of effective treatments.
Biomedical Research Center of Aragón (CIBA), Aragón Health Research Institute (IIS Aragón), University of Zaragoza , Zaragoza , Spain.
Diego
D
Sánchez-Martínez
Biomedical Research Center of Aragón (CIBA), Aragón Health Research Institute (IIS Aragón), University of Zaragoza , Zaragoza , Spain.
Pilar M
PM
Lanuza
Immunogenetics and HLA, Instituto de Investigación Sanitaria Puerta de Hierro , Majadahonda , Spain.
Natalia
N
Gómez
Immunity and infection Lab, IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain.
Aura
A
Muntasell
Immunogenetics and HLA, Instituto de Investigación Sanitaria Puerta de Hierro , Majadahonda , Spain.
Elisa
E
Cisneros
Immunogenetics and HLA, Instituto de Investigación Sanitaria Puerta de Hierro , Majadahonda , Spain.
Manuela
M
Moraru
Hospital Clínico Universitario Lozano Blesa, Instituto Aragonés de Ciencias de la Salud (IACS)/Aragón Health Research Institute (IIS Aragón) , Zaragoza , Spain.
Gemma
G
Azaceta
Department of Biochemistry and Molecular and Cellular Biology, Aragón Health Research Institute (IIS Aragón), University of Zaragoza , Zaragoza , Spain.
Alberto
A
Anel
Hospital Clínico Universitario Lozano Blesa, Instituto Aragonés de Ciencias de la Salud (IACS)/Aragón Health Research Institute (IIS Aragón), Zaragoza, Spain; Nanoscience Institute of Aragon (INA), University of Zaragoza, Zaragoza, Spain.
Luis
L
Martínez-Lostao
INSERM U1183, Université de Montpellier 1, UFR Médecine, Montpellier, France; Institute for Regenerative Medicine and Biotherapy (IRMB), CHU Montpellier, Montpellier, France.
Martin
M
Villalba
Hospital Clínico Universitario Lozano Blesa, Instituto Aragonés de Ciencias de la Salud (IACS)/Aragón Health Research Institute (IIS Aragón) , Zaragoza , Spain.
Luis
L
Palomera
Immunity and infection Lab, IMIM (Hospital del Mar Medical Research Institute) , Barcelona , Spain.
Carlos
C
Vilches
Unidad de Citogenética Molecular/Servicio de Hematología, Hospital Universitario Puerta de Hierro-Majadahonda , Madrid , Spain.
José A
JA
García Marco
Biomedical Research Center of Aragón (CIBA), Aragón Health Research Institute (IIS Aragón), University of Zaragoza, Zaragoza, Spain; Nanoscience Institute of Aragon (INA), University of Zaragoza, Zaragoza, Spain; Aragón I+D Foundation (ARAID), Government of Aragon, Zaragoza, Spain; Department of Microbiology, Preventive Medicine and Public Health, University of Zaragoza, Zaragoza, Spain.
Julián
J
Pardo
allogeneic NK cells; bad prognosis leukemia; chronic lymphocytic leukemia; leukemia resistance; mismatch