Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia.
The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF-α and IFN-γ production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-α production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-α and IFN-γ production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival.
krezvani@mdanderson.org.
Kate
K
Stringaris
Takuya
T
Sekine
Ahmad
A
Khoder
Abdullah
A
Alsuliman
Bonnie
B
Razzaghi
Ruhena
R
Sargeant
Jiri
J
Pavlu
Gill
G
Brisley
Hugues
H
de Lavallade
Anushruthi
A
Sarvaria
David
D
Marin
Stephan
S
Mielke
Jane F
JF
Apperley
Elizabeth J
EJ
Shpall
A John
AJ
Barrett
Katayoun
K
Rezvani
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D060828:Induction Chemotherapy; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D055607:Receptors, Natural Killer Cell / Q000378:metabolism; D012074:Remission Induction; D017211:Treatment Failure; D016896:Treatment Outcome; D055815:Young Adult
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D055607:Receptors, Natural Killer Cell