https://orcid.org/0000-0003-3216-8759
Key Points
AML blasts suppress NK cells by secreting PGE2, leading to a blockade of LCK and consequently to a functional blockade of NK cells.
Therapeutic approaches with antibodies targeting AML blasts in combination with the blockade of PGE2 signaling enable NK killing.
Abstract
Loss of anticancer natural killer (NK) cell function in patients with acute myeloid leukemia (AML) is associated with fatal disease progression and remains poorly understood. Here, we demonstrate that AML blasts isolated from patients rapidly inhibit NK cell function and escape NK cell-mediated killing. Transcriptome analysis of NK cells exposed to AML blasts revealed increased CREM expression and transcriptional activity, indicating enhanced cyclic adenosine monophosphate (cAMP) signaling, confirmed by uniform production of the cAMP-inducing prostanoid prostaglandin E2 (PGE2) by all AML-blast isolates from patients. Phosphoproteome analysis disclosed that PGE2 induced a blockade of lymphocyte-specific protein tyrosine kinase (LCK)–extracellular signal-regulated kinase signaling that is crucial for NK cell activation, indicating a 2-layered escape of AML blasts with low expression of NK cell-activating ligands and inhibition of NK cell signaling. To evaluate the therapeutic potential to target PGE2 inhibition, we combined Fcγ-receptor-mediated activation with the prevention of inhibitory PGE2 signaling. This rescued NK cell function and restored the killing of AML blasts. Thus, we identify the PGE2-LCK signaling axis as the key barrier for NK cell activation in 2-layered immune escape of AML blasts that can be targeted for immune therapy to reconstitute anticancer NK cell immunity in patients with AML.
References
1.
Merino
A
, Zhang
B
, Dougherty
P
, et al. Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming
. J Clin Invest
. 2019
;129
(9
):3770
-3785
.2.
Lanier
LL
. Up on the tightrope: natural killer cell activation and inhibition
. Nat Immunol
. 2008
;9
(5
):495
-502
.3.
Wolf
NK
, Kissiov
DU
, Raulet
DH
. Roles of natural killer cells in immunity to cancer, and applications to immunotherapy
. Nat Rev Immunol
. 2023
;23
(2
):90
-105
.4.
Colucci
F
, Di Santo
JP
, Leibson
PJ
. Natural killer cell activation in mice and men: different triggers for similar weapons?
. Nat Immunol
. 2002
;3
(9
):807
-813
.5.
Vivier
E
, Nunes
JA
, Vely
F
. Natural killer cell signaling pathways
. Science
. 2004
;306
(5701
):1517
-1519
.6.
Vivier
E
, Rebuffet
L
, Narni-Mancinelli
E
, Cornen
S
, Igarashi
RY
, Fantin
VR
. Natural killer cell therapies
. Nature
. 2024
;626
(8000
):727
-736
.7.
Dohner
H
, Weisdorf
DJ
, Bloomfield
CD
. Acute myeloid leukemia
. N Engl J Med
. 2015
;373
(12
):1136
-1152
.8.
Pizzolo
G
, Trentin
L
, Vinante
F
, et al. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission
. Br J Cancer
. 1988
;58
(3
):368
-372
.9.
Tratkiewicz
JA
, Szer
J
. Loss of natural killer activity as an indicator of relapse in acute leukaemia
. Clin Exp Immunol
. 1990
;80
(2
):241
-246
.10.
Carlsten
M
, Jaras
M
. Natural killer cells in myeloid malignancies: immune surveillance, NK cell dysfunction, and pharmacological opportunities to bolster the endogenous NK cells
. Front Immunol
. 2019
;10
:2357
.11.
Stringaris
K
, Sekine
T
, Khoder
A
, et al. Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia
. Haematologica
. 2014
;99
(5
):836
-847
.12.
Bjorklund
AT
, Clancy
T
, Goodridge
JP
, et al. Naive donor NK cell repertoires associated with less leukemia relapse after allogeneic hematopoietic stem cell transplantation
. J Immunol
. 2016
;196
(3
):1400
-1411
.13.
Costello
RT
, Sivori
S
, Marcenaro
E
, et al. Defective expression and function of natural killer cell–triggering receptors in patients with acute myeloid leukemia
. Blood
. 2002
;99
(10
):3661
-3667
.14.
Paczulla
AM
, Rothfelder
K
, Raffel
S
, et al. Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion
. Nature
. 2019
;572
(7768
):254
-259
.15.
Büchner
T
, Hiddemann
W
, Wörmann
B
, et al. Double induction strategy for acute myeloid leukemia: the effect of high-dose cytarabine with mitoxantrone instead of standard-dose cytarabine with daunorubicin and 6-thioguanine: a randomized trial by the German AML Cooperative Group
. Blood
. 1999
;93
(12
):4116
-4124
.16.
Dufour
A
, Schneider
F
, Metzeler
KH
, et al. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome
. J Clin Oncol
. 2010
;28
(4
):570
-577
.17.
Parekh
S
, Ziegenhain
C
, Vieth
B
, Enard
W
, Hellmann
I
. The impact of amplification on differential expression analyses by RNA-seq
. Sci Rep
. 2016
;6
:25533
.18.
Fauriat
C
, Just-Landi
S
, Mallet
F
, et al. Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction
. Blood
. 2007
;109
(1
):323
-330
.19.
Zajac
M
, Zaleska
J
, Dolnik
A
, et al. Analysis of the PD-1/PD-L1 axis points to association of unfavorable recurrent mutations with PD-L1 expression in AML [abstract]
. Blood
. 2016
;128
(22
):1685
.20.
Collins
PL
, Cella
M
, Porter
SI
, et al. Gene regulatory programs conferring phenotypic identities to human NK cells
. Cell
. 2019
;176
(1-2
):348
-360.e12
.21.
Oberlies
J
, Watzl
C
, Giese
T
, et al. Regulation of NK cell function by human granulocyte arginase
. J Immunol
. 2009
;182
(9
):5259
-5267
.22.
Mussai
F
, De Santo
C
, Abu-Dayyeh
I
, et al. Acute myeloid leukemia creates an arginase-dependent immunosuppressive microenvironment
. Blood
. 2013
;122
(5
):749
-758
.23.
Baumann
T
, Dunkel
A
, Schmid
C
, et al. Regulatory myeloid cells paralyze T cells through cell-cell transfer of the metabolite methylglyoxal
. Nat Immunol
. 2020
;21
(5
):555
-566
.24.
Messai
Y
, Noman
MZ
, Hasmim
M
, Escudier
B
, Chouaib
S
. HIF-2alpha/ITPR1 axis: a new saboteur of NK-mediated lysis
. Oncoimmunology
. 2015
;4
(2
):e985951
.25.
Rosain
J
, Neehus
AL
, Manry
J
, et al. Human IRF1 governs macrophagic IFN-gamma immunity to mycobacteria
. Cell
. 2023
;186
(3
):621
-645.e33
.26.
Santosa
EK
, Kim
H
, Rückert
T
, et al. Control of nutrient uptake by IRF4 orchestrates innate immune memory
. Nat Immunol
. 2023
;24
(10
):1685
-1697
.27.
Gotthardt
D
, Trifinopoulos
J
, Sexl
V
, Putz
EM
. JAK/STAT cytokine signaling at the crossroad of NK cell development and maturation
. Front Immunol
. 2019
;10
:2590
.28.
Lamas
B
, Vergnaud-Gauduchon
J
, Goncalves-Mendes
N
, et al. Altered functions of natural killer cells in response to L-arginine availability
. Cell Immunol
. 2012
;280
(2
):182
-190
.29.
Kalinski
P
. Regulation of immune responses by prostaglandin E 2
. J Immunol
. 2012
;188
(1
):21
-28
.30.
van Galen
P
, Hovestadt
V
, Wadsworth Ii
MH
, et al. Single-cell RNA-seq reveals AML hierarchies relevant to disease progression and immunity
. Cell
. 2019
;176
(6
):1265
-1281.e24
.31.
Rah
SY
, Kwak
JY
, Chung
YJ
, Kim
UH
. ADP-ribose/TRPM2-mediated Ca2+ signaling is essential for cytolytic degranulation and antitumor activity of natural killer cells
. Sci Rep
. 2015
;5
:9482
.32.
Tyanova
S
, Temu
T
, Sinitcyn
P
, et al. The Perseus computational platform for comprehensive analysis of (prote)omics data
. Nat Methods
. 2016
;13
(9
):731
-740
.33.
Mesecke
S
, Urlaub
D
, Busch
H
, Eils
R
, Watzl
C
. Integration of activating and inhibitory receptor signaling by regulated phosphorylation of Vav1 in immune cells
. Sci Signal
. 2011
;4
(175
):ra36
.34.
Billadeau
DD
, Upshaw
JL
, Schoon
RA
, Dick
CJ
, Leibson
PJ
. NKG2D-DAP10 triggers human NK cell–mediated killing via a Syk-independent regulatory pathway
. Nat Immunol
. 2003
;4
(6
):557
-564
.35.
Courtney
AH
, Amacher
JF
, Kadlecek
TA
, et al. A phosphosite within the SH2 domain of Lck regulates its activation by CD45
. Mol Cell
. 2017
;67
(3
):498
-511.e6
.36.
Yamaguchi
H
, Hendrickson
WA
. Structural basis for activation of human lymphocyte kinase Lck upon tyrosine phosphorylation
. Nature
. 1996
;384
(6608
):484
-489
.37.
Kästle
M
, Merten
C
, Hartig
R
, et al. Tyrosine 192 within the SH2 domain of the Src-protein tyrosine kinase p56Lck regulates T-cell activation independently of Lck/CD45 interactions
. Cell Commun Signal
. 2020
;18
(1
):183
.38.
Bergmann
L
, Schui
DK
, Brieger
J
, Weidmann
E
, Mitrou
PS
, Hoelzer
D
. The inhibition of lymphokine-activated killer cells in acute myeloblastic leukemia is mediated by transforming growth factor-beta 1
. Exp Hematol
. 1995
;23
(14
):1574
-1580
.39.
Zhang
Q
, Bi
J
, Zheng
X
, et al. Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity
. Nat Immunol
. 2018
;19
(7
):723
-732
.40.
Bae
DS
, Hwang
YK
, Lee
JK
. Importance of NKG2D-NKG2D ligands interaction for cytolytic activity of natural killer cell
. Cell Immunol
. 2012
;276
(1-2
):122
-127
.41.
Bournazos
S
, Gupta
A
, Ravetch
JV
. The role of IgG Fc receptors in antibody-dependent enhancement
. Nat Rev Immunol
. 2020
;20
(10
):633
-643
.42.
Pemmaraju
N
, Lane
AA
, Sweet
KL
, et al. Tagraxofusp in blastic plasmacytoid dendritic-cell neoplasm
. N Engl J Med
. 2019
;380
(17
):1628
-1637
.43.
Gauthier
L
, Virone-Oddos
A
, Beninga
J
, et al. Control of acute myeloid leukemia by a trifunctional NKp46-CD16a-NK cell engager targeting CD123
. Nat Biotechnol
. 2023
;41
(9
):1296
-1306
.44.
Olson
JA
, Zeiser
R
, Beilhack
A
, Goldman
JJ
, Negrin
RS
. Tissue-specific homing and expansion of donor NK cells in allogeneic bone marrow transplantation1
. J Immunol
. 2009
;183
(5
):3219
-3228
.45.
Chretien
AS
, Devillier
R
, Granjeaud
S
, et al. High-dimensional mass cytometry analysis of NK cell alterations in AML identifies a subgroup with adverse clinical outcome
. Proc Natl Acad Sci U S A
. 2021
;118
(22
):e2020459118
.46.
Segerberg
F
, Lambert
M
, Sanz-Ortega
L
, Andersson
A
, Childs
RW
, Carlsten
M
. Improved leukemia clearance after adoptive transfer of NK cells expressing the bone marrow homing receptor CXCR4R334X
. Hemasphere
. 2023
;7
(11
):e974
.47.
Bednarski
JJ
, Zimmerman
C
, Berrien-Elliott
MM
, et al. Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant
. Blood
. 2022
;139
(11
):1670
-1683
.48.
Ciurea
SO
, Kongtim
P
, Srour
S
, et al. Results of a phase I trial with haploidentical mbIL-21 ex vivo expanded NK cells for patients with multiply relapsed and refractory AML
. Am J Hematol
. 2024
;99
(5
):890
-899
.49.
Berrien-Elliott
MM
, Cashen
AF
, Cubitt
CC
, et al. Multidimensional analyses of donor memory-like NK cells reveal new associations with response after adoptive immunotherapy for leukemia
. Cancer Discov
. 2020
;10
(12
):1854
-1871
.50.
Wang
D
, Zhu
X
, Sun
Z
. The mechanism of activated TGF-β1 inhibiting GVL effects of bone marrow NK cells leading to early relapse after transplantation [abstract]
. Blood
. 2020
;136
(suppl 1
):48
-49
.51.
Borst
L
, van der Burg
SH
, van Hall
T
. The NKG2A-HLA-E axis as a novel checkpoint in the tumor microenvironment
. Clin Cancer Res
. 2020
;26
(21
):5549
-5556
.52.
Bexte
T
, Albinger
N
, Al Ajami
A
, et al. CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells
. Nat Commun
. 2024
;15
(1
):8439
.53.
Tettamanti
S
, Pievani
A
, Biondi
A
, Dotti
G
, Serafini
M
. Catch me if you can: how AML and its niche escape immunotherapy
. Leukemia
. 2022
;36
(1
):13
-22
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