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Multiple myeloma (MM) is characterized by
immune dysfunctions including defective dendritic cell (DC) and T cell
functions, which are associated with poor clinical outcomes. Therefore, drugs
that improve the immune status are as considered effective therapeutic
strategies for MM. Lenalidomide (LEN), as an immunomodulatory drug (IMiD), is
an important backbone drug for MM treatment to quantitatively and qualitatively enhance several immune cell types. Plasmacytoid DCs (pDCs) represent a
major source of type-I interferons (IFNs) that not only directly induce cell
arrest, but also activate immune effectors to induce clearance of pathological
cells in protective anti-tumor and anti-viral immunities. Some functions of IFNs overlap with those of
IMiDs. Thus, pDCs are an important cellular component for recovery of
the immune status by MM therapy using IMiDs. This review focuses on the immunological link between IMiDs and
pDCs in the immune dysfunctions of MM. pDCs are localized frequently in bone
marrow (BM) of MM patients and BM-infiltrating pDCs display unfavorable
functions to prolong survival of MM cells by their reduced ability to promote
T-cell proliferation in the BM milieu. However, CpG-oligodeoxynucleotide (ODN)
stimulation, while triggering the IFN response, restores T-cell responses of
pDCs and represses MM cell growth. Proteasome inhibitor bortezomib suppresses
type-I IFN production by pDCs. Moreover, non-uniformity of LEN functions
against pDCs in recent reports might be attributed to different experimental
settings. However, LEN at the clinical concentration range might not, at least,
inhibit strongly, but sustain the ability of pDCs to produce type-I IFNs in MM
treatment. These effects may explain
the low incidence of herpes zoster viral infection observed during LEN
treatment compared with bortezomib treatment. IMiDs orchestrate the
activities of wide varieties of immune
cell types, including sustaining pDC functions, thereby leading to
amplification of a positive-immune axis to eliminate MM cells.
Keywords: lenalidomide,
Pomalidomide, IMiDs, Plasmacytoid DCs, Type-I IFNs, Multiple myeloma
Abbreviations:
MM: Multiple myeloma; DCs: Dendritic cells; IMiDs: Immunomodulatory-drugs;
LEN: Lenalidomide; POM: Pomalidomide (POM); pDC: Plasmacytoid dendritic cells
(pDCs); CTL: Cytotoxic T lymphocytes, NK: Natural killer; IFN: Interferons; BM:
Bone marrow; Tregs: Regulatory T cells; IL: Interleukin (IL); PBMC: Peripheral
blood mononuclear cells; TLR: Toll-like receptor; PFS: Progression-free
survival (PFS); OS: Overall survival
INTRODUCTION
Multiple myeloma (MM) is a multistep malignancy of plasma
cells in bone marrow (BM), leading to bone destruction, renal dysfunction and
disruption of normal BM functions reflected by anemia. MM is generally regarded
as incurable. However, treatment of MM has been evolving with the introduction
of new drugs such as immunomodulatory drugs (IMiDs), including lenalidomide
(LEN) and pomalidomide (POM), proteasome inhibitors and antibody drugs. Thus,
the 5-year survival rate has increased gradually because of new drug
development over the last decade.
MM is characterized by immune dysfunctions, including
defective dendritic cell (DC) and T cell functions, which are associated with
poor clinical outcomes.
IMiDs
enhance a wide variety of immune cell
types quantitatively and
qualitatively and are important backbone drugs for MM treatment. Plasmacytoid DCs (pDCs) represent
the major source of type-I interferons (IFNs) that not only directly induce
cell cycle arrest, but also activate immune effectors to eliminate pathological
cells in protective anti-tumor and anti-viral immunities. Because some functions of type-I IFNs overlap with those
of IMiDs, pDCs are an important cellular component as an additional cellular target of IMiDs
for recovery of the immune status by MM therapy. This review focuses on pDC functiona in the immune dysfunctions
of MM and immunological cooperation of IMiDs and pDCs in MM treatment.
MM involves immune dysfunctions
MM is
characterized by immune dysfunctions [1-3]. Aberrant
production and release of monoclonal proteins from MM cells into the
bloodstream and urine causes reduced normal immunoglobulin secretion and
increased susceptibility to infection. In terms of other cellular functions,
reduced T-cell immunity has been reported during MM disease progression [4,5], such as an
increased number of regulatory T cells (Tregs) associated with poor clinical
outcomes [6,7]. PD-L1 and
PD-1 expression are increased in MM cells and immune effector cells [i.e.,
cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells], respectively, in
MM patients [1,8]. In
addition, DCs are pivotal in orchestrating both innate and acquired immunities
as a commander of the immune regulatory system and a series of analyses have
clarified the functional plasticity of DCs to induce Th1 or Th2 response.
Recent studies have demonstrated several defective immunological properties in
DCs of MM patients with a lack of CD80 and CD86 molecules, functional inability
of antigen presentation, and accumulation of both immature and inactivated DCs
in BM [2,3]. Other
mechanisms lead to tumor escape and immune tolerance, which are apparently
dependent on high release of transforming growth factor‐β, interleukin (IL)-10,
IL-6, vascular endothelial growth factor, and FAS/FASL in the myeloma BM
environment, resulting in DC dysfunction in T-cell activation and proliferation
[9]. These
findings explain, at least in part, the defective immune functions in MM
patients, which are associated with a poor prognosis.
Functions of plasmacytoid DCs in MM patients
In humans, DCs consist of two major subsets:
CD11c+ myeloid DCs and pDCs. They play distinct roles in innate and
acquired immunities by their expression of specialized cytokines and molecules.
Although the essential function of DCs is to
prime naïve and memory T cells to differentiate into inflammatory Th1, Th2, or
Th17 cells in acquired immunity, pDCs paradoxically have an intrinsic capacity
to prime naive T cells to differentiate into IL-10-producing Tregs at a mature
stage [10]. pDCs
suppress inflammatory responses against pathogens [11] and
allergens [12] and promote
oral tolerance [13] and
engraftment of hematopoietic stem cells [14] as well as
vascularized grafts [15].
Immunosuppressive effects of tumor-infiltrating pDCs has been demonstrated in
solid tumors [16,17] and pDC
infiltration correlates with poor clinical disease outcomes of breast cancer [18].
Furthermore, among hematopoietic malignancies, chronic myeloid leukemia
patients with high CD86+ pDC counts have
a higher risk of relapse after treatment discontinuation [19].
Additionally, in MM patients, pDCs induce growth and prolong survival of MM
cells in the milieu of pathological BM [20]. Thus, pDCs
have been implicated in contribution, at least in part, to immune dysfunctions
due to the reduced ability of pDCs to induce T cell proliferation in BM [20] and
peripheral blood [21] of MM
patients.
In addition
to the antigen-presenting function in acquired immunity, pDCs have a unique
aspect as a type-I IFN-producer in innate immunity. Although they comprise only
a small fraction of peripheral blood mononuclear cells (PBMCs), pDCs represent
a major source of type-I IFNs in the blood and lymphoid tissues of both humans
and mice [22,23]. Human pDCs
respond to viral infection through their selective expression of toll-like
receptor (TLR)7 and TLR9 [24], which
sense viral RNA and DNA, respectively, and dedicate a large proportion of their
transcriptional machinery to producing type-I IFNs [25]. Accumulating evidence suggests that
type-I IFNs enhance immune effector cells [26-28], leading to
enhancement of the entire immune system including CTLs, NK cells, neutrophils,
and monocytes. Thus, pDCs exert protective anti-viral inflammatory effects
through secretion of vast amounts of type-I IFNs that not only directly inhibit
viral replication, but also activate an immune network of cytotoxic effector
cells to induce clearance of infected cells. These pDC/type-I IFN-mediated
immune processes may contribute to both tumor cell cycle arrest and activation
of immune effectors to eliminate several types of malignancies. Indeed, type-I
IFNs trigger direct anti-tumor cytotoxicity in B-cell malignancies by inducing
apoptosis [29] and inhibit
cell proliferation [30,31].
Furthermore, recombinant IFN-a
has shown activity against B-cell hematologic neoplasms by immune activation of
cytotoxic effector cells [32]. The
efficacy of recombinant IFN-a
in patients with MM was reported before drug development of IMiDs and
proteasome inhibitors [32,33]. Type-I
IFN-based maintenance regimens, despite some conflicting results, have also
shown some clinical benefits [34]. TLR
stimulation by CpG-ODNs to induce large amounts of type-I IFNs restores the in vitro T-cell response of pDCs from MM
patients and blocks MM cell line growth [20]. In this
context, pDCs may be a target of immunotherapy to substitute for recombinant
IFN treatment.
Numbers of plasmacytoid DCs in MM patients
The number
of immune cells in MM patients has been reported to be small. However, no
conclusion has been
reached regarding blood DC numbers in MM
patients. One report showed a decreased number of blood pDCs in MM patients
compared with healthy donors [21] and pDC
depletion with downregulation of the IKZF1 protein level by LEN treatment [35], whereas
three other studies found that blood pDC numbers in MM patients were nearly
identical to those in normal donors [2,20,36]. Studies
have shown that the MM genome is complex, and that MM patients are extremely
diverse with genomic heterogeneity [37].
Accordingly, the controversy about the blood pDC numbers in MM patients might
be attributed to the fact that all of these studies were conducted with a small
number of cases with heterogeneity of the disease status or progression phase.
One of these
studies has also evaluated the distribution of pDCs in MM patients [20]. Although
there is no significant difference in pDC numbers between BM and peripheral
blood in healthy donors, increased pDCs are observed in BM compared with
peripheral blood in MM patients. The other possibility for the non-uniformity
of the pDC number is migration from blood to BM due to different MM progression
phase. Considering the defective function of pDCs in BM of MM patients in
regards to the ability for T cell proliferation, frequent localization of pDCs
in BM may cause the immune dysfunctions in MM.
IMiDs enhance immune
functions
LEN and POM have both direct tumoricidal and
indirect immunomodulatory effects. Both drugs are important backbone drugs for
MM and continuous treatment with LEN until diseases progression confers a
survival benefit for MM patients [38]. The immune dysfunctions are associated
with a poor prognosis of MM patients and clinical outcomes can be improved by
recovery of the immune status [6,7]. Therefore, immunotherapies or drugs that
improve the immune status are considered to be effective therapeutic
strategies, making IMiDs backbone drugs for MM because of their immunopotentiating
activity as describe below. LEN has been shown to improve humoral immunity with
non-neoplastic globulin recovery in MM patients, especially patients exhibiting
with long-term therapeutic benefits [39]. Furthermore, patients with humoral
responses improved by LEN have better outcomes of both PFS and OS [39,40].
Considering that myeloma is a malignancy of plasma cells and based on the
pathology of humoral immune dysfunction, restoring humoral immunity by IMiDs
treatment may improve clinical outcomes.
Studies have
revealed a wide array of immune cell types targeted by IMiDs. LEN and POM
promote the proliferation of some immune effector cell types in vivo. The total percentage of
proliferating S-phase CD4+ T cells, CD8+ T cells, and NK cells increases after administration of LEN
in MM patients [41]. In addition to this quantitative enhancement,
several studies have shown that LEN induces qualitative activation of several
immune cell types. For example, LEN augments NK cell cytotoxicity and CTL
activity [42-47], and inhibits the proliferation and functions of
Treg cells [48,49]. In addition, POM increases cytotoxic effector
cells (CTLs/NK cells) quantitatively and qualitatively in vivo [50].
Moreover, LEN downregulates PD-L1 on primary
MM cells and PD-1 on NK cells and CTLs of MM patients, leading to enhanced
immune responses induced by immune
checkpoint blockade [1,8]. Thus, the function of IMiDs, which facilitates the
attack of MM cells by activated immune effectors, is supported by the elaborate
immunostimulatory effect, which is relevant to the treatment of MM patients
with immune dysfunctions. Some of these functions in the immune system appear
to overlap with IFN functions. Therefore, validating the effect of IMiDs to
target the pDC-IFN pathway might be useful and may provide a rationale for the
clinical use of IMiDs in MM patients.
IMiDs for
plasmacytoid DC functions
There is evidence of immunomodulatory
activities of LEN and POM in mouse conventional DCs [47,51] and a
synergistic effect of DC vaccination in murine models of MM [52-54] and colon
cancer [55]. In this
context, DCs would be important cellular components for recovery of the immune
status by MM treatment, especially therapy using IMiDs. Several recent studies have elucidated the functions of IMiDs in human DC
subsets [35,36,56,57], especially
pDCs [20,35,36]. These findings provide new insights into a possible mechanism through
which IMiDs operates as a pleiotropic immunomodulator in MM patients.
Cytlak. et
al. demonstrated that ikaros family zinc finger 1 (IKZF1) deficiency induces
pDC depletion using PBMCs from individuals carrying an IKZF1 mutation [35].
They also reported that the absolute pDC count showed a significant positive
correlation with the IKZF1 protein level in MM patients treated with LEN, which
induces proteasomal degradation of IKZF1, and that IKZF1 deficiency or LEN
treatment induced less secretion of IFN-a by pDCs. They concluded that LEN has a negative effect
on pDC functions and differentiation. In contrast, we have recently
demonstrated that LEN significantly enhances IFN-a production by pDCs stimulated with low concentrations of
CpG-ODN, but not an optimal high concentration [36]. Clinical pharmacokinetics
show that clinical peak plasma LEN concentrations of MM patients administered
10 or 25 mg oral LEN are around 1.2 mM
(311 ng/mL) and 2.7 mM (714
ng/mL), respectively [58]. The former study showed that IFN-a-producing cell numbers were decreased
modestly among pDCs treated with increasing concentrations (0.1, 1 or 10 μM) of
LEN. Meanwhile, the latter study showed that 0.1–3 μM LEN (covering the
clinical in vivo plasma concentration range of oral LEN administration) did not
affect pDC survival, although pDCs were susceptible to the cytotoxic effects of
proteasome inhibitor bortezomib. Moreover, IFN-a production by pDCs in response to CpG-ODN 2216 was not
decreased significantly after exposure to a clinical concentration range of LEN
(0.01-3 μM).
In the
former experimental setting, a TLR agonist cocktail consisting of CpG-ODN, poly
(I: C), CL075, and LPS was added to total PBMCs, and then the number of
cytokine-producing cells was analyzed by intracellular staining of each cell
type [35]. This was a condition under which pDCs were affected by cytokines
produced by other cell types, such as IL-10 and TNF. Furthermore, CpG-ODN 2216
was added at a very high concentration of 7.5 uM. In the latter experimental
setting, pDCs purified from PBMCs were applied to an IFN-a production assay. In addition, to address
the possibility that LEN could not further enhanced IFN-α production by pDCs
because of exhaustion following maximal CpG-ODN 2216 stimulation, a low and
suboptimal concentration of CpG-ODN 2216 (0.1 µM) was examined to stimulate
pDCs [36]. Although pDCs rapidly produce vast amounts of type-I IFNs following
stimulation by viruses or CpG-ODN [22], pDCs are incapable of mounting a
secondary type-I IFN response for further stimulation [25]. In this context,
pDCs do not retain a sufficient capacity to further produce type-I IFNs by the
maximal response to optimal stimulation. The latter experiments showed that LEN
promotes the residual capacity of pDCs to produce IFN-a by suboptimal stimulation. Thus, LEN at a clinical
concentration range might, at least, not inhibit strongly, but could possibly
sustain the ability of pDCs to produce type-I IFNs in MM treatment.
Clinical relevance of IMiDs regarding pDC functions
pDCs as antigen-presenting cells with a
tolerogenic function are considered to play a partial role in the immune
dysfunctions of MM patients as mentioned above. However, pDCs trigger
activation of the immune system as a part of their anti-viral and anti-tumor
responses through type-I IFN production. Type-I IFNs and IMiDs appear to have
some overlapping functions in the immune system. Thus, immunomodulatory
functions of IMiDs in MM cells might work synergistically to mediate the effect
of type-I IFNs to enhance cellular and humoral immunities [42-49]. In this
sense, considering the capability of IMiDs to activate immune effectors without
strong inhibition of pDC functions or to potentially enhance the ability of
pDCs to produce IFN-a by suboptimal stimulation, IMiDs may function as preservers of endogenous
IFN and are therefore positive immunomodulators that activate surrounding
immune cells in addition to their direct tumoricidal effects (Figure 1).
Thus, the immunological link between IMiDs
and pDCs may participate in the immune processes in MM during treatment with
IMiDs. In contrast to IMiDs, proteasome inhibitor bortezomib has been shown to
suppress immune responses and type-I IFN production by pDCs [36, 59-61]. Consistent
with the function of IMiDs to preserve endogenous type-I IFNs, there is
relatively low incidence of herpes zoster viral infection during LEN treatment
compared with bortezomib treatment [62-64]. Continuous treatment with low-dose
LEN as a maintenance therapy after stem cell transplantation contributes to
better survival of MM patients [65, 66]. The clinical pharmacokinetics of LEN
shows a gentle curve from the peak plasma concentration. LEN at 10 mg
administered orally to MM patients results in an approximate clinical peak
plasma concentration of 1.2 µM [58]. Even at a low concentration (0.1–1.0 mM, equivalent to the clinical
plasma concentration range resulting from oral administration of 10 mg LEN),
LEN sustains IFN-a
production by pDCs [36]. This finding suggests that low-dose LEN (i.e., 10 mg
oral administration) functions as an immunostimulator during maintenance
therapy and sustains the immune status. This could be one of the advantages of
long-term continuous therapy with low-dose LEN.
CONCLUSION
IMiDs orchestrate the
activities of a wide variety of
both innate and acquired immune cell types, including pDC functions, leading to amplification of
a positive immune axis able to eliminate MM cells (Figure 1). Immunotherapies
or drugs that improve the immune status are considered as effective therapeutic
strategies, making IMiDs backbone drugs for MM.
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