• Antibody-mediated inhibition of MICA/B shedding promotes the phagocytosis of leukemia cells by macrophages.

  • Romidepsin synergizes with antibody-mediated inhibition of MICA/B shedding by inducing leukemia cells to upregulate the MICA/B expression.

Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA/B) are stress proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in 2 models in immunocompetent mice. Macrophages were essential for therapeutic efficacy, and 7C6 triggered antibody-dependent phagocytosis of AML cells. Furthermore, we found that romidepsin, a selective histone deacetylase inhibitor, increased MICB messenger RNA in AML cells and enabled subsequent stabilization of the translated protein by 7C6. This drug combination substantially increased surface MICA/B expression in a human AML line, pluripotent stem cell-derived AML blasts and leukemia stem cells, as well as primary cells from 3 untreated patients with AML. Human macrophages phagocytosed AML cells following treatment with 7C6 and romidepsin, and the combination therapy lowered leukemia burden in a humanized model of AML. Therefore, inhibition of MICA/B shedding promotes macrophage-driven immunity against AML via Fc receptor signaling and synergizes with an epigenetic regulator. These results provide the rationale for the clinical testing of this innovative immunotherapeutic approach for the treatment of AML.

1.
Siegel
RL
,
Miller
KD
,
Fuchs
HE
,
Jemal
A.
Cancer statistics, 2021 [published correction appears in CA Cancer J Clin. 2021;71(4):359]
.
CA Cancer J Clin.
2021
;
71
(
1
):
7
-
33
.
2.
Davids
MS
,
Kim
HT
,
Bachireddy
P
, et al;
Leukemia and Lymphoma Society Blood Cancer Research Partnership
.
Ipilimumab for patients with relapse after allogeneic transplantation
.
N Engl J Med.
2016
;
375
(
2
):
143
-
153
.
3.
Daver
N
,
Garcia-Manero
G
,
Basu
S
, et al
.
Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/refractory acute myeloid leukemia: a nonrandomized, open-label, phase II study
.
Cancer Discov.
2019
;
9
(
3
):
370
-
383
.
4.
Daver
NG
,
Garcia-Manero
G
,
Konopleva
MY
, et al
.
Azacitidine (AZA) with nivolumab (Nivo), and AZA with Nivo+ ipilimumab (Ipi) in relapsed/refractory acute myeloid leukemia: a non-randomized, prospective, phase 2 study
.
Blood.
2019
;
134
(
suppl 1
):
830
.
5.
Ley
TJ
,
Miller
C
,
Ding
L
, et al;
Cancer Genome Atlas Research Network
.
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia
.
N Engl J Med.
2013
;
368
(
22
):
2059
-
2074
.
6.
Tran
E
,
Robbins
PF
,
Rosenberg
SA.
‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations
.
Nat Immunol.
2017
;
18
(
3
):
255
-
262
.
7.
Godwin
CD
,
McDonald
GB
,
Walter
RB.
Sinusoidal obstruction syndrome following CD33-targeted therapy in acute myeloid leukemia
.
Blood.
2017
;
129
(
16
):
2330
-
2332
.
8.
Raulet
DH
,
Gasser
S
,
Gowen
BG
,
Deng
W
,
Jung
H.
Regulation of ligands for the NKG2D activating receptor
.
Annu Rev Immunol.
2013
;
31
(
1
):
413
-
441
.
9.
Bauer
S
,
Groh
V
,
Wu
J
, et al
.
Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA
.
Science.
1999
;
285
(
5428
):
727
-
729
.
10.
Boutet
P
,
Agüera-González
S
,
Atkinson
S
, et al
.
Cutting edge: the metalloproteinase ADAM17/TNF-alpha-converting enzyme regulates proteolytic shedding of the MHC class I-related chain B protein
.
J Immunol.
2009
;
182
(
1
):
49
-
53
.
11.
Chitadze
G
,
Lettau
M
,
Bhat
J
, et al
.
Shedding of endogenous MHC class I-related chain molecules A and B from different human tumor entities: heterogeneous involvement of the “a disintegrin and metalloproteases” 10 and 17
.
Int J Cancer.
2013
;
133
(
7
):
1557
-
1566
.
12.
Yang
FQ
,
Liu
M
,
Yang
FP
, et al
.
Matrix metallopeptidase 2 (MMP2) mediates MHC class I polypeptide-related sequence A (MICA) shedding in renal cell carcinoma
.
Actas Urol Esp.
2014
;
38
(
3
):
172
-
178
.
13.
Salih
HR
,
Rammensee
HG
,
Steinle
A.
Cutting edge: down-regulation of MICA on human tumors by proteolytic shedding
.
J Immunol.
2002
;
169
(
8
):
4098
-
4102
.
14.
Kaiser
BK
,
Yim
D
,
Chow
IT
, et al
.
Disulphide-isomerase-enabled shedding of tumour-associated NKG2D ligands
.
Nature.
2007
;
447
(
7143
):
482
-
486
.
15.
Salih
HR
,
Antropius
H
,
Gieseke
F
, et al
.
Functional expression and release of ligands for the activating immunoreceptor NKG2D in leukemia
.
Blood.
2003
;
102
(
4
):
1389
-
1396
.
16.
Baumeister
SH
,
Murad
J
,
Werner
L
, et al
.
Phase I trial of autologous CAR T cells targeting NKG2D ligands in patients with AML/MDS and multiple myeloma
.
Cancer Immunol Res.
2019
;
7
(
1
):
100
-
112
.
17.
Xing
S
,
Ferrari de Andrade
L.
NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells
.
Clin Transl Immunology.
2020
;
9
(
12
):
e1230
.
18.
Ferrari de Andrade
L
,
Tay
RE
,
Pan
D
, et al
.
Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity
.
Science.
2018
;
359
(
6383
):
1537
-
1542
.
19.
Wesely
J
,
Kotini
AG
,
Izzo
F
, et al
.
Acute myeloid leukemia iPSCs reveal a role for RUNX1 in the maintenance of human leukemia stem cells
.
Cell Rep.
2020
;
31
(
9
):
107688
.
20.
Kotini
AG
,
Chang
CJ
,
Chow
A
, et al
.
Stage-specific human induced pluripotent stem cells map the progression of myeloid transformation to transplantable leukemia
.
Cell Stem Cell.
2017
;
20
(
3
):
315
-
328.e7
.
21.
Klussmeier
A
,
Massalski
C
,
Putke
K
, et al
.
High-throughput MICA/B genotyping of over two million samples: workflow and allele frequencies
.
Front Immunol.
2020
;
11
:
314
.
22.
Law
LW.
Characterization of an influence affecting growth of transplantable leukemias in mice
.
Cancer Res.
1944
;
4
(
4
):
257
-
260
.
23.
Warner
NL
,
Moore
MA
,
Metcalf
D.
A transplantable myelomonocytic leukemia in BALB-c mice: cytology, karyotype, and muramidase content
.
J Natl Cancer Inst.
1969
;
43
(
4
):
963
-
982
.
24.
Ferrari de Andrade
L
,
Kumar
S
,
Luoma
AM
, et al
.
Inhibition of MICA and MICB shedding elicits NK-cell-mediated immunity against tumors resistant to cytotoxic T cells
.
Cancer Immunol Res.
2020
;
8
(
6
):
769
-
780
.
25.
Ferrari de Andrade
L
,
Ngiow
SF
,
Stannard
K
, et al
.
Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma
.
Cancer Res.
2014
;
74
(
24
):
7298
-
7308
.
26.
Wu
J
,
Song
Y
,
Bakker
AB
, et al
.
An activating immunoreceptor complex formed by NKG2D and DAP10
.
Science.
1999
;
285
(
5428
):
730
-
732
.
27.
Groh
V
,
Steinle
A
,
Bauer
S
,
Spies
T.
Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells
.
Science.
1998
;
279
(
5357
):
1737
-
1740
.
28.
Groh
V
,
Rhinehart
R
,
Randolph-Habecker
J
,
Topp
MS
,
Riddell
SR
,
Spies
T.
Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells
.
Nat Immunol.
2001
;
2
(
3
):
255
-
260
.
29.
Guillerey
C
,
Ferrari de Andrade
L
,
Vuckovic
S
, et al
.
Immunosurveillance and therapy of multiple myeloma are CD226 dependent [published correction appears in J Clin Invest. 2015;125(7):2904]
.
J Clin Invest.
2015
;
125
(
5
):
2077
-
2089
.
30.
Seedhom
MO
,
Mathurin
KS
,
Kim
SK
,
Welsh
RM.
Increased protection from vaccinia virus infection in mice genetically prone to lymphoproliferative disorders
.
J Virol.
2012
;
86
(
11
):
6010
-
6022
.
31.
Pilones
KA
,
Aryankalayil
J
,
Babb
JS
,
Demaria
S.
Invariant natural killer T cells regulate anti-tumor immunity by controlling the population of dendritic cells in tumor and draining lymph nodes
.
J Immunother Cancer.
2014
;
2
(
1
):
37
.
32.
Majeti
R
,
Chao
MP
,
Alizadeh
AA
, et al
.
CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells
.
Cell.
2009
;
138
(
2
):
286
-
299
.
33.
Bournazos
S
,
Wang
TT
,
Dahan
R
,
Maamary
J
,
Ravetch
JV.
Signaling by antibodies: recent progress
.
Annu Rev Immunol.
2017
;
35
(
1
):
285
-
311
.
34.
Hilpert
J
,
Grosse-Hovest
L
,
Grünebach
F
, et al
.
Comprehensive analysis of NKG2D ligand expression and release in leukemia: implications for NKG2D-mediated NK cell responses
.
J Immunol.
2012
;
189
(
3
):
1360
-
1371
.
35.
Paczulla
AM
,
Rothfelder
K
,
Raffel
S
, et al
.
Absence of NKG2D ligands defines leukaemia stem cells and mediates their immune evasion [published correction appears in Nature. 2019;572(7770):E19]
.
Nature.
2019
;
572
(
7768
):
254
-
259
.
36.
Lanotte
M
,
Martin-Thouvenin
V
,
Najman
S
,
Balerini
P
,
Valensi
F
,
Berger
R.
NB4, a maturation inducible cell line with t(15;17) marker isolated from a human acute promyelocytic leukemia (M3)
.
Blood.
1991
;
77
(
5
):
1080
-
1086
.
37.
Armeanu
S
,
Bitzer
M
,
Lauer
UM
, et al
.
Natural killer cell-mediated lysis of hepatoma cells via specific induction of NKG2D ligands by the histone deacetylase inhibitor sodium valproate
.
Cancer Res.
2005
;
65
(
14
):
6321
-
6329
.
38.
Skov
S
,
Pedersen
MT
,
Andresen
L
,
Straten
PT
,
Woetmann
A
,
Odum
N.
Cancer cells become susceptible to natural killer cell killing after exposure to histone deacetylase inhibitors due to glycogen synthase kinase-3-dependent expression of MHC class I-related chain A and B
.
Cancer Res.
2005
;
65
(
23
):
11136
-
11145
.
39.
Zhang
C
,
Wang
Y
,
Zhou
Z
,
Zhang
J
,
Tian
Z.
Sodium butyrate upregulates expression of NKG2D ligand MICA/B in HeLa and HepG2 cell lines and increases their susceptibility to NK lysis
.
Cancer Immunol Immunother.
2009
;
58
(
8
):
1275
-
1285
.
40.
Diermayr
S
,
Himmelreich
H
,
Durovic
B
, et al
.
NKG2D ligand expression in AML increases in response to HDAC inhibitor valproic acid and contributes to allorecognition by NK-cell lines with single KIR-HLA class I specificities
.
Blood.
2008
;
111
(
3
):
1428
-
1436
.
41.
Takenaka
K
,
Prasolava
TK
,
Wang
JC
, et al
.
Polymorphism in Sirpa modulates engraftment of human hematopoietic s tem cells
.
Nat Immunol.
2007
;
8
(
12
):
1313
-
1323
.
42.
Ardolino
M
,
Azimi
CS
,
Iannello
A
, et al
.
Cytokine therapy reverses NK cell anergy in MHC-deficient tumors
.
J Clin Invest.
2014
;
124
(
11
):
4781
-
4794
.
43.
Klimek
VM
,
Fircanis
S
,
Maslak
P
, et al
.
Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes
.
Clin Cancer Res.
2008
;
14
(
3
):
826
-
832
.
44.
Craddock
C
,
Tholouli
E
,
Vicente
SM
, et al
.
Safety and clinical activity of combined romidepsin and azacitidine therapy in high risk acute myeloid leukemia: preliminary results of the Romaza Trial
.
Blood.
2017
;
130
(
suppl 1
):
2581
.
45.
Schlenk
RF
,
Krauter
J
,
Raffoux
E
, et al
.
Panobinostat monotherapy and combination therapy in patients with acute myeloid leukemia: results from two clinical trials
.
Haematologica.
2018
;
103
(
1
):
e25
-
e28
.
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