Summary
Natural killer (NK) cells are cytotoxic lymphocytes contributing in innate immune responses that recognize and kill virus-infected and tumor cells without prior stimulation. Several clinical trials have indicated that NK cell-based immunotherapy represents a promising antitumor immunotherapeutic approach due to their key role in mediating graft versus leukemic effect against hematological malignancies, particularly acute myeloid leukemia. However, the antitumor activity of NK cells is inhibited as a result to immune-evasion mechanisms developed by malignant cells through alterations in the expression of activating and inhibitory receptors and their ligands, as well as secretion of soluble NK-inhibitory mediators. Until now, the exact molecular mechanisms involved in these alterations are still not defined.Introduction
Natural killer (NK) cells are lymphocytes of the innate immune system which have the ability to recognize tumors and virus-infected cells without prior specific sensitization.[1,2] NK cell functions are regulated by the expression of numerous inhibitory and activating receptors which bind to ligands on healthy or transformed cells.[1-3] The antitumor activity of NK cells is mediated through direct cytotoxic function as well as regulation of other immune cells by cytokine-secreting function. NK cells play a key role in mediating graft versus leukemic (GvL) effect against hematological malignancies, particularly acute myeloid leukemia (AML).[4,5] However, tumor cells can develop immunosuppressive mechanisms to escape NK cell-mediated immunity. Hence, maintaining or improving NK cell performance is considered a major challenge. In this review, we focus on the different mechanisms involved in the evasion of hematological malignancies from NK cells surveillance. Futhermore, we will mention the different approaches used to restore and improve the efficacy of anti-tumor function of NK cells against hematological malignancies.
NK Cell Biology
NK cells are lymphocytes arising from the lymphoid
origin which are considered as the third largest population
of lymphocytes following T and B cells encompassing
approximately 10-15% of all peripheral blood
lymphocytes.[6] However, NK cells are considered as
critical cells of the innate immune system due to their
ability to kill the target cells directly without specific
immunization.[3,7] Based on the expression of CD56
molecule, NK cells are defined as CD56+ lymphocytes.
[6] Phenotypically, NK cells can be divided into many
subsets based on the surface expression of CD56, CD16, inhibitory receptors and/or activating receptors.
[6] In general, the major subpopulations of NK cells
are CD56bright CD16-/+ (5-10% of NK cells) and CD56dim
CD16+ NK cells (90-95% of NK cells).[6,8]
NK Cell Cytotoxicity
NK cells play a key role in immuno-surveillance and
host defense against certain virus-infected or transformed
cells mediated by direct cytolysis as well as
regulation of the effector functions of other cytotoxic
immune cells.[9-11] NK cell functions are controlled
by a balance between activating and inhibitory signals
provided by a varied group of activating receptors as
(NKG2D, DNAM-1, NKp30, NKp44, and NKp46)
and inhibitory receptors as NKG2A.[12] In general,
NK cells can recognize abnormal cells through two
models: Missing-self recognition and stress-induced
recognition because abnormal cells as tumor cells can
change their surface phenotype by losing the expression
of human leukocyte antigen (HLA) class I molecules
and/or upregulating damage-associated proteins.
[13] Numerous damage-associated proteins have been
expressed by tumor cells such as MICA and MICB
binding with NKG2D, ligands of NKp30 as B7-H6, a
mixed-lineage leukemia protein which is a ligand of
NKp44, and CD155 and CD112 which interact with
DNAM-1.[14] Consequently, NK cell activating receptors
bind with their specific ligands expressed on the
target cells resulting in lysis of their target cells. Alongside
their activation by tumor cells and pathogens, NK
cells can be directly or indirectly regulated through
signals from other immune cells such as dendritic cells
(DCs), macrophages, CD4+ T cells during the immune
response.[14] Then, activated NK cells have the ability
to kill their target cells though a variety of mechanisms,
including cytolytic granule-dependent exocytosis
pathway, signaling through the tumor necrosis
factor (TNF) death receptor family members such as
FAS (CD95) and TNF-related apoptosis-inducing ligand,
the release of cytokines IFN-γ and TNF-α, and antibody
dependent cell cytotoxicity (ADCC) via CD16.
[15] Besides the cytotoxicity mediated by NK cells, immune
response can be regulated by NK cells through
the recruitment of other immune cells.
NK Cells and AML
Leukemias are cancers starting in cells that would normally
develop into different types of blood cells. AML,
one type of leukemias, is a heterogeneous clonal disorder of HSC characterized by accumulation of immature,
non-functional myeloid precursors (blasts) in the bone
marrow and blood without the ability to differentiate
normally and to respond to normal regulators of proliferation.[16] In general, patients with newly diagnosed
AML, cytotoxic chemotherapy results in CR in approximately
60-80%.[17] However, most of them relapse and
about 40-45% of patients achieving CR remain alive at
5 years. To minimize the relapse and improve the survival
rate of in patients, immunotherapy is used in combination
with standard therapy.[18,19] NK cells play a
principal role in the immunosurveillance of hematological
malignancies by direct and indirect killing of tumor
cells. Several clinical trials have been used NK cells as
adoptive immunotherapy based on the alloreactivity of
donor's NK cells to treat the hematological malignancies
and solid tumors.[20-25] However, tumor cells can
develop various mechanisms to escape immunosurveillance
of NK cell and other effector cells.[26,27]
Mechanisms of AML Escape from NK Cell Immunity
Although the cytotoxic activity of NK cells against
leukemia cells and their beneficial role in immunotherapy,
many tumors including AML can evade the immunosurveillance
of NK cell by destroying the precise
balance between inhibitory and activating signals.[28-
32] Commonly, AML cells are able to escape NK cell
immunosurveillance through various mechanisms: i)
alteration of NK cells, ii) immunosuppressive properties
of AML cells, and iii) interactions with other immune
cells (Fig. 1).
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Alterations of NK Cell By AML
AML cells are capable to alter the expression of NK cell
receptors and their ligands, resulting in a significant
impairment of NK cell functions, however, the molecular
mechanisms responsible for these alterations are
still unknown.
Alterations of the Expression of NK Cell Receptors
Several reports have shown a clear decrease in the expression
of NK activating receptors on circulating NK
cells of AML patients such as natural cytotoxic receptors,
NCRs (NKp30, NKp44 and NKp46), NKG2D,
and DNAM-1.[28,30,31,33-35] These alterations are
associated with impaired anti-leukemic activity of NK
cells, a decreased cytokine production, and risk of tumor
relapse. Notably, Fauriat et al.,[30] (2007) showed
that NCRs downregulation on NK cells was associated with poor prognosis for AML patients, and significantly
lower 5-year survival rates than their NCRbright
counterparts. Interestingly, the phenotypic and functional
abnormalities of NK cells are partially or totally
restored in patients achieving remission, which suggest
that the presence of AML cells is responsible for NK
cells abnormalities.[30] Moreover, Olive's team in 2017
showed a strong correlation between NKp46 expression
on NK cells of AML patients at diagnosis and the
clinical outcomes after allogeneic stem cell transplantation.
They found that patients with high expression
of NKp46 at diagnosis had better progression-free survival
and overall survival (OS) than patients with low
expression of NKp46.[36] Regarding the expression of
inhibitory receptors, it is clear that failure to achieve
remission in AML patients is strongly associated with
overexpression of NKG2A and inhibitory KIRs.[31,33]
Alterations of the Expression of NK Cell Receptors
Ligands
Another strategy by which AML can escape from NK
cell immunosurveillance is decreasing the expression
and shedding of surface ligands for various NK cell
activating receptors on AML cells themselves.[34,37-40] For example, leukemic blasts are characterized
by a sharp decrease in the expression of MICA/B and
ULBPs (ligands of NKG2D), CD48 (a ligand for 2B4),
NCR-specific ligands, and DNAM-1 ligands (CD112/
CD155).[34,38,39,41,42] These alterations were associated
with reduction of the effector functions of NK cells
and OS among those patients. On other hand, DNAM-
1 ligands (CD112 and CD155) are highly expressed on
AML blasts of patients younger than 65 years. However,
NK recognition and killing of leukemic blasts is
reduced due to downregulation of DNAM-1 on NK
cells of AML patients, hypothesizing a converse relationship
between DNAM-1 ligands expression on
leukemic blasts and DNAM-1 expression on NK cells.
[43] Besides the classical alterations of the expression
of NK receptors and their ligands in AML, Olive's
team reported alteration in the maturation profile of
NK cells in AML patients. They found three different
groups of AML patients based on NK maturation profile:
hypomaturation, intermediate maturation, and hypermaturation.
Interestingly, the findings revealed that
patients with hypomaturation profile have decreased
OS and relapse-free survival compared to patients with
intermediate and hypermaturation.[44]
Alterations of NK Cell at Genetic Level
Some attempts were performed at gene level to try to
identify the molecular mechanisms of NK functions
defect in hematological malignancies. In this context,
Costello's team aimed to realize the mechanisms underlying
NCRs down-regulation in NK cells from AML
patients.[32] They found that AML-NK cells showed
a specific transcriptomic signature compared to NK
cells from healthy volunteers, disappeared by NK cells
expansion. Although the gene expression of E26 transformation-
specific 1 (ETS-1) transcription factor (a
potential regulatory element of NCRs expression) was
decreased in presence of AML blasts, the expression
of ETS-1 and NCRs was restored following AML-NK
cells expansion. This proposes that ETS-1 may regulate
NCRs expression.[32] In addition, miRNAs, which play
an important role in fundamental NK cell biology,[45]
can be well accepted to participate in many aspects of
AML, including proliferation, differentiation, survival,
apoptosis and invasion by targeting oncogenes or tumor
suppressors.[46,47] A study showed a selective loss
of immature NK cells subset and a clear reduction in the
cytolytic granules containing perforin and granzyme B
among NK cells in leukemic mice and the NK cells in
leukemic mice showed lower levels of T-bet and Eomes,
critical transcription factors for terminal NK cell differentiation.
They demonstrated that these results are related
to miR-29b overproduction, a negative regulator
of T-bet and Eomes, in NK cells of leukemic mice because
deletion of miR-29b in NK cells reversed these alterations.[48] A recent study found that the expression
of CD48 molecule is down-regulated on the surface of
NK cells in AML patients.[49] CD48 is expressed on
the surface of lymphocytes including NK cells and participates
in activation and differentiation pathways in
these cells. The results showed that down-regulation of
CD48 in AML patients was associated with decreasing
the cytotoxic activity of NK cells.[49]
Immunosuppressive Properties of AML Blasts
Besides the phenotypic and functional alterations of
NK cells, AML blasts are able to diminish NK cell immunosurveillance
by other immunosuppressive factors.
For example, a study found an overexpression of
CD137 ligand (CD137L) and glucocorticoid-induced
tumor necrosis factor receptor (TNFR)-related protein
ligand (GITRL) on AML blasts, where these molecules
are ligands for TNFR family.[50,51] Engagement of
CD137L and GITRL with their receptors on human NK
cells is directly associated with impairing NK cell-mediated
killing and IFN-γ secretion or indirectly via secretion of IL-10 by AML cells. Oppositely, they showed
that both CD137 and GITR mediate a stimulatory signal
in mouse NK cells after their binding with CD137L
and GITRL, respectively.[50,51] Cytotoxic functions of
NK cells are also impaired by TGF-β, which is secreted
by AML blast as well as by regulatory T (Treg) cells,
myeloid derived suppressor cells and other stromal
cells in the tumor microenvironment.[52,53]
Alterations of Interaction Between NK Cells and
Other Immune Cells
Cellular interactions between NK cells and other immune
cells are also altered in AML patients resulting
in more possibilities of immune escape. NK cells play a
key role in regulation of DCs by killing immature DCs
to limit inflammation and inappropriate T cell tolerization.
Fauriat and his colleagues (2005) have noticed the
inability of NK cells from AML patients to kill immature
DCs which might result in an abnormal interaction
between T cells and immature DCs and induction
of tolerogenic T cells.[54] Further, the number of Treg
cells, which are the predominant immune suppressor
cells, are increased among AML patients compared to
healthy donors, while their numbers are reduced in patients
with complete remission (CR).[55]
Restoration of NK Cell Cytotoxic Functions
Whereas impaired NK cells are associated with the
progression of AML, recovery and boosting the effector
functions of NK cells are essential for the control
and eradication of AML. In general, there are different
approaches used to restore and enhance the effectiveness
of anti-tumor function of NK cells, including cytokines,
monoclonal antibodies (mAbs), and adoptive
transfer of NK cells.[14,26,56-59]
Cytokines
Several cytokines have been confirmed to enhance NK
cell proliferation and/or cytotoxicity against several
types of tumors. Cytokines are used for this purpose either
by direct infusion of cytokines in vivo to boost the
autologous NK cell numbers and functions or by in vitro
incubation of allogeneic NK cells with cytokines before
adoptive NK cell immunotherapy. IL-2 is the first cytokine
approved for use in patients to improve NK cells
activity, where it restored NK cell receptor expression
and increased NK cell activity against autologous AML
cells in vitro.[60] However, infusion of IL-2 into patients
was accompanied by limited clinical outcomes because IL-2 activates not only NK cells but also Treg cells, which
express CD25 (high affinity receptor for IL-2) that can
compete with NK cells for IL-2, and subsequently suppress
their effector function.[61] In addition, IL-15 was
used to activate NK cells with less toxicity.[62] IL-15 has
been reported to control development, homeostasis and
cytotoxicity of NK cells, which can be presented to NK
cells in vivo through several cell types, including monocytes,
macrophages and DCs.[63] Infusion of IL-15 into
patients increased the cell numbers of circulating NK
cells and upregulated the expression of the activating
NK cell receptor NKp30, which augmented NK cell cytotoxicity
in AML patients.[35,64]
mAbs and Checkpoint Inhibitors
mAbs can realize anti-tumor effects by modifying the
activity of their target proteins and by redirecting the
effector immune cells to cancer cells. mAbs treatment
based on NK cells includes mAbs which target tumorassociated
antigens to induce NK cell, and mAbs which
target and block immune checkpoint proteins to enhance
NK cell cytotoxicity.[14,26,57] By targeting tumor-
associated antigens, a specific immune response
can be achieved against the tumor cells. In the case of
NK cells, these antibodies directly target tumor-associated
antigens and also bind to Fc?RIIIA (CD16a) receptor
expressed by NK cells to induce NK-mediated
ADCC. Consistent with the meaning, studies showed
that monoclonal anti-CD123 antibody (CD123 is overexpressed
on AML stem cells showing anti-leukemic
activity) improved the binding to CD16a and enhanced
the anti-leukemic activity of NK cells against AML
xenograft models.[65,66] Further, Koerner et al.[67]
(2017) found that an Fc-optimized CD133 antibody had
a greater affinity to NK cells and more cytotoxic activity
for NK cells without relevant toxicity to hematopoietic
progenitors in a human AML xenograft model.
The second strategy based on mAbs to recover NK cell effector functions is using targeted mAbs to block specific immune checkpoint proteins to enhance the cytotoxic activity of NK cells. One of these inhibitory proteins is NKG2A, an inhibitory receptor expressed in NK cells and binds with HLA-E ligand. The expression of HLA-E is often upregulated in some cancer cells to escape from NK cell cytotoxicity. In addition, NKG2A expression on tumor-infiltrating NK cells has increased in cancer cells.[68,69] As a result, blocking NKG2A by a humanized antibody called monalizumab improves the cytotoxic activity of NK cells in mice engrafted with primary leukemia cells as well as against HLA-E+ target cells.[70,71] Another checkpoint affecting the functional activity of NK cells is programmed cell death protein 1 (PD-1) which was recently discovered in a mature CD56dim NK cells where its expression significantly suppresses NK function against PD-1 ligand expressing tumor targets.[72,73] In addition, the expression of programmed cell death ligand-1 (PD-L1) is observed in AML blasts.[74] PD-1 antibodies such as pembrolizumab and nivolumab, preventing PD-1/ PD-L1 interaction, have been developed and their effect to enhance endogenous NK cell cytotoxic function remains attractive.[75] Interestingly, blocking PD-1 or PD-L1 increases the cytotoxic activity of NK cells, and decreases the growth of some tumors in xenograft models.[76,77] In AML, nivolumab in combination with idarubicin and cytarabine decreased the progression of AML in patients with newly diagnosed AML and also increased the OS.[78]
NK Cell-Based Adoptive Immunotherapy
,The strategy of using NK cells as adoptive immunotherapy
depends on the valuable effects of NK cell alloreactivity
which is induced by the mismatch between
HLA class I molecules on recipient cells and KIRs on
donor NK cells. Several clinical reports have shown
that donor NK cell alloreactivity is a key therapeutic element
in the success of transplant and killing leukemia
through GvL effect without development of graft versus
host disease as well as controlling infections.[79,80]
In general, donor-derived NK cells are mainly obtained
from donor PBMCs by separating protocols; however,
obtaining sufficient numbers of NK cells from PBMCs
to achieve a therapeutic effect has been a major limitation.[81] Therapeutically, a phase I clinical trial showed
that infusion of IL-15 plus IL-21 stimulated NK cells
which were given after hematopoietic stem cell transplantation
(HSCT) reduced progression of leukemia
compared with patients who have subjected to HSCT
without NK cell infusion.[82] Moreover, infusion
of multiple doses of NK cells expanded ex vivo with
feeder cells was effective in minimizing leukemia relapse.
A present study showed that infusion of IL-2 activated
NK cells into patients with hematologic malignancies
2 months following HSCT was associated with
increasing the expression of activating receptors on the
reconstituting NK cells as well as increasing degranulation
and cytokine production.[83] After follow-up,
a CR of hematologic malignancies was observed in 11
patients out of 16 treated patients.
Conclusion
NK cells are a specific group of lymphocytes playing a key role in the innate immune responses against virus-infected cells as well as different types of cancer. Although NK cells play a major role in immunosurveillance against AML cells, it was demonstrated that NK cells in AML patients have impaired anti-leukemic activity due to multiple mechanisms of innate immune escape, including down-regulation of activating receptors expression, up-regulation of inhibitory NKG2A expression, down-regulation of NK-activating ligands, and secretion of soluble NK-inhibitory factors as well as other immunosuppressant mechanisms. However, the specific molecular mechanisms involved in these alterations are still not well defined. Hence, there is a persistent need for complete understanding of how AML escapes the natural defenses of immune system.Peer-review: Externally peer-reviewed.
Conflict of Interest: The authors declare no conflicts of interest.
Financial Support: The authors received no financial support for the publication of this article.
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