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Immunosuppressive Microenvironment in the Progression of Multiple Myeloma: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Matthew Ho.

The immunosuppressive multiple myeloma bone marrow microenvironment consists of myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like macrophages (M2 TAMs), N2 neutrophils, regulatory T cells (Tregs), regulatory B cells (Bregs), and plasmacytoid dendritic cells (pDCs). 

  • multiple myeloma
  • bone marrow microenvironment
  • immunotherapy

1. Introduction

One key step in tumorigenesis is the ability of cancer to evade immune surveillance, the process by which a competent immune system recognizes and eliminates tumor cells [23][1]. MM clones and subclones that harbor mutations that allow them to escape immune destruction are selected for growth within the BM microenvironment [24][2]. Additionally, MM cells maintain a highly immunosuppressive BM microenvironment by promoting the expansion of myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like macrophages (M2 TAMs), N2 neutrophils, regulatory T cells (Tregs), regulatory B cells (Bregs), and plasmacytoid dendritic cells (pDCs) [8,25][3][4].
The immunosuppressive MM BM microenvironment consists of myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like macrophages (M2 TAMs), N2 neutrophils, regulatory T cells (Tregs), regulatory B cells (Bregs), and plasmacytoid dendritic cells (pDCs) [8][3]. Multiple immunotherapeutic approaches have been developed including antibody-based therapies (e.g., monoclonal antibodies, bispecific antibodies) and cellular therapies (e.g., CAR T cells, CAR-NK cells, CAR-M) to target MM within the context of the BM. Despite high response rates in patients treated with multiple prior lines of therapy, one limitation to current immunotherapeutic approaches is the lack of durability and the high rates of relapse. Studies aimed at uncovering the mechanism of MM immune evasion and effector cell exhaustion are currently underway.

2. Regulatory T Cells (Tregs)

Tregs are a subset of CD4+ T cells that express forkhead box P3 (FoxP3) and function to suppress immune response to maintain self-tolerance [26][5]. FoxP3 is the main transcription factor enabling the function of Tregs, and Tregs are immunophenotypically characterized by CD3+CD4+CD25hiCD127loFoxP3+ [27][6]. In the context of the immunosuppressive MM BM microenvironment, Tregs inhibit MM-specific T-cell effector functions through direct cell-to-cell contact and the secretion of IL10, TGFβ, and IL35, as well as cytolytic granzymes and perforins, to inhibit and/or kill immune effector cells [28,29,30][7][8][9]. TGFβ is not only immunosuppressive but under the right conditions and together with IL2, has been shown to be able to induce the expression of FoxP3 in effector cells resulting in their functional conversion to Tregs [31][10]. In vitro studies have also shown that direct contact with MM cells is able to induce the development of CD4+CD25+FoxP3+ Tregs from an initial population of CD4+CD25−FoxP3− cells, mediated by an inducible T-cell co-stimulator (ICOS) on T cells and their ligands (ICOS-L) expressed on MM cells [32][11]. Notably, one study showed that a lenalidomide and dexamethasone combination is able to reduce ICOS-L expression on MM cells and inhibit Treg differentiation measured by decreased FoxP3 expression [33][12]. However, other studies have reported conflicting results that lenalidomide increases Treg frequency in patients with MM and chronic lymphocytic leukemia [34,35,36,37][13][14][15][16]. This discrepancy in response to lenalidomide treatment may be dose- and time-dependent where short-term treatment induces Treg but prolonged treatment with increasing doses of lenalidomide inhibits Tregs [34,35][13][14]. Another potential explanation could be due to IMiD’s ability to downregulate CXCR4 expression on Tregs [38][17]. CXCR4-expressing Tregs are attracted to the MM BM microenvironment by cytokines such as stromal-derived-factor-1ɑ (SDF-1α), CXCR4 ligand [38][17]. Downregulation of CXCR4 may therefore allow Tregs to leave the BM and accumulate within the peripheral blood. Other anti-MM agents such as dexamethasone, cyclophosphamide, and daratumumab have also been shown to induce Treg apoptosis [33,39,40,41,42,43,44][12][18][19][20][21][22][23].
Indoleamine (IDO) is a cytosolic enzyme that degrades tryptophan into kynurenine (KYN). IDO-mediated KYN production promotes Treg development, stabilization, and activation, while suppressing effector T cells [45,46][24][25]. KYN is overexpressed in the serum and bone marrow of patients with MM (compared to healthy controls) and also higher in patients with ISS stage II/III disease (compared to ISS stage I) [46][25]. IDO was found to be expressed by CD138+ MM cells, as well as MM patient-derived BMSCs that were stimulated with IFNγ [46][25]. High IDO and KYN expression correlated with increased Treg accumulation with the MM BM microenvironment [46][25]. Conversely, inhibition of IDO with D,L-1-methyl-tryptophan inhibited MM-mediated Treg expansion and promoted T helper type 1 (Th1) differentiation [46][25]. Engagement of programmed cell death 1 (PD1) on the surface of Th1 cells by PD1 ligand (PDL1)-overexpressing cells or coated beads can also induce Tregs in vitro [47,48][26][27]. A proliferation-inducing ligand (APRIL), which is highly secreted by myeloid precursor cells (e.g., megakaryocytes, eosinophils, monocytes) and osteoclasts within the MM BM microenvironment [49][28], canonically binds B-cell maturation antigen (BCMA) on the MM-cell surface to drive survival and proliferation, has also been shown to bind a transmembrane activator, calcium modulator, and cyclophilin ligand interactor (TACI) on Tregs to drive MM-mediated Treg differentiation, proliferation, and survival [50,51][29][30].
The role of Tregs in MM pathogenesis and progression remains unclear, and conflicting studies have shown increased [29[8][31][32][33][34],52,53,54,55], decreased [36[15][35],56], or unchanged [57,58][36][37] Treg frequency in patients with MM. This lack of consistency is likely due to differences in the compartment studied (peripheral blood vs bone marrow), different immunophenotypic definitions of Tregs (CD4+FoxP3+, CD4+CD25hi, CD4+CD25+FoxP3+, CD4+CD25+CD127−), and interpatient tumor heterogeneity. The compartment matters as one study showed that Tregs are enriched in the peripheral blood (but not BM) of patients with treatment-naïve MM when compared to MGUS and controls [59][38]. The same study, however, did show that activated and memory Tregs were enriched in both the peripheral blood and BM of patients with treatment-naïve MM but that resting Tregs were significantly higher in controls [59][38]. Although this corresponded with increased terminally differentiated CD8+ effector cells seen in patients with treatment-naïve MM and increased central memory CD8+ T cells in controls, the study did not show a difference in the in vitro suppressive capacity of Tregs isolated from treatment-naïve MM compared to controls [59][38]. Specifically, Tregs were isolated from MM and controls and co-cultured with CD3/CD28 bead-activated PBMCs, and flow cytometry was used to analyze markers of activated T cells (i.e., CD69 and CD154 expression on CD4+ and CD8+ T cells). MM-derived Tregs did not significantly decrease the proportion of CD69 or CD154-expressing activated T cells when compared with healthy donor-derived Tregs [59][38].
Finally, studies comparing the frequency of Tregs in the BM versus peripheral blood of patients with MM have also reported inconsistent results, with some studies reporting higher frequencies in the MM BM [59,60,61][38][39][40] and others reporting similar peripheral blood and BM Treg frequencies [52,55][31][34].

3. Plasmacytoid Dendritic Cells (pDCs)

Plasmacytoid dendritic cells (pDCs) are a specialized subset of CD123 and CD303 co-expressing dendritic cells derived from BM hematopoietic stem cells [62][41]. Physiologically, pDCs are part of innate immunity and regulate anti-viral responses [62][41]. Upon stimulation by viral RNA and DNA, pDCs produce IFNγ and differentiate into professional antigen-presenting cells to stimulate T cells of the adaptive immune system [62][41]. pDCs eventually leave the BM and migrate directly into primary lymphoid organs and T cell-rich areas of secondary lymphoid tissues where they reside normally [62][41]. However, it has been reported in a number of human tumors that malignant cells recruit pDCs to the tumor microenvironment to help with immune tolerance [63][42]. This preferential accumulation of pDCs within the BM (as opposed to peripheral blood) is similarly seen in MM [64][43]. Compared to healthy donor-derived BM samples, MM patient-derived BM samples had higher frequencies of pDCs, and while no significant difference in pDC number was observed between healthy BM vs peripheral blood, an increased number of pDCs were noted in MM BM vs MM peripheral blood [64][43]. Importantly, in vitro co-cultures show that pDCs isolated from MM BM were able to induce proliferation and confer bortezomib resistance in MM cell lines [64][43]. Additionally, pDCs isolated from the MM BM showed significantly impaired ability to trigger T-cell proliferation (assessed by 3H-thymidine incorporation assay) when compared to normal pDCs [64][43].
pDCs highly express PDL1, which is further enhanced by pDC-MM interaction, and this leads to inhibition of T- and NK-cell function [65][44]. Consistent with this, blockade of the PDL1-PD1 interaction with the anti-PDL1 antibody was able to restore MM-specific cytotoxic T-cell and NK-cell activity [65][44]. MM-derived pDCs were also able to trigger MM proliferation and confer drug resistance to bortezomib in vitro [64][43]. Mechanistically, pDC-MM contact stimulates the secretion of IL10, VEGF, CD40L, IL8, IL15, IL6, and MCP1 [64][43]. This growth-promoting effect can be abrogated by disrupting NF-κB through the inhibition of the B-cell activating factor (BAFF)/APRIL and receptor activator of NF-κB (RANK)/RANKL signaling [64][43]. Additionally, because pDCs strongly expresses CD38, daratumumab induces strong depletion of pDCs [66][45].

4. Myeloid-Derived Suppressor Cells (MDSCs)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that have been shown to accumulate in both the peripheral blood and BM of patients with MM [67][46]. There are two types of MDSCs: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC) that are distinguished by CD14 expression [68][47]. M-MDSCs (CD11b+CD14+CD33+HLA-DRlow/−), in particular, are enriched in patients with newly diagnosed and relapsed MM compared with patients in remission, and high levels of M-MDSCs have been found to correlate with MM progression and treatment resistance [69][48]. Functionally, MDSCs induce T-cell apoptosis by producing nitric oxide and suppress T-cell function by producing reactive oxygen and nitrogen species, as well as deplete the microenvironment of L-arginine and L-cysteine, which are used to produce the CD3ζ-chain, a component of the T-cell receptor [70,71,72,73][49][50][51][52].
In vitro co-culture experiments show that exposure of peripheral blood mononuclear cells (PBMCs) obtained from healthy donors to direct contact with MM cells, conditioned media from MM cell lines, and plasma from newly diagnosed patients can induce the development of MDSCs [69,74,75][48][53][54]. The C-C motif chemokine ligand 5 (CCL5) and macrophage migration inhibitory factor (MIF) have recently been found to be key soluble mediators of MDSC induction and are secreted by MM cells [76][55]. The same study found that both lenalidomide and pomalidomide were able to decrease MM expression of CCL5 (through cereblon-dependent pathways) and MIF (through cereblon-independent pathways) [76][55]. Both IMiDs were also able to decrease expression of the C-C motif chemokine receptor 5 (CCR5) and induce interferon regulatory factor 8 (IRF8) expression, a negative regulator of differentiation towards MDSCs [76][55].

5. Cancer-Associated Fibroblasts (CAFs)

Cancer-associated fibroblasts (CAFs) are a heterogeneous population of CD45− BM stromal cells expressing different levels of fibroblast specific protein 1 (FSP1), alpha smooth muscle actin (αSma), and fibroblast activating protein (FAP) [77,78][56][57]. CAFs have recently been shown to mediate MM proliferation and therapeutic resistance through the production of various cytokines (e.g., IL6, TGFβ), chemokines (e.g., SDF-1), and pro-inflammatory and pro-angiogenic factors (e.g., VEGF) [77,78][56][57]. Consistent with this, BM CAFs are enriched in patients with newly-diagnosed and relapsed MM compared to patients with MGUS or non-MM controls [78][57]. In vivo studies with syngeneic 5T33MM and xenograft mouse models show that MM cells are able to induce CAF proliferation [78][57]. Direct contact between MM cells and CAFs through CXCL12/CXCR4 and other integrins is necessary to facilitate the tumor-promoting functions of CAFs [77][56]. Strategies aimed at depleting CAFs using monoclonal antibodies and CAR T cells are currently being studied preclinically and will be discussed later.

6. Tumor-Associated M2-like Macrophages (M2 TAMs)

Mature macrophages are identified by the surface markers CD16, CD68, CD115, CD163, and CD312, and represent a major aspect of the innate immune system [79][58]. Beyond phagocytosis of pathogens and apoptotic cells, macrophages have both tumor promoting and tumor killing effects depending on environmental cues [80][59]. Two flavors of macrophages exist depending on function: (1) M1 macrophages, which are classically activated by interferon-γ (IFNγ) or lipopolysaccharide (LPS), facilitate tumor killing through phagocytosis, the release of nitric oxide and reactive oxygen species, as well as proinflammatory cytokines (i.e., IL1, IL6, IL8, IL12, TNFα) [80,81[59][60][61],82], and (2) the IL4 dependent alternatively-activated M2 macrophages, which are anti-inflammatory [83,84][62][63]. M2 macrophages support tumor growth by secreting vascular endothelial growth factor (VEGF), transforming growth factor-β (TGFβ), IL10, and also through expression of PD-L1 [83,84,85][62][63][64].
Phenotypically and functionally similar to M2 macrophages are CD163 and CD206 expressing tumor-associated M2-like macrophages (M2 TAMs) [86][65]. TAMs originate from peripheral blood monocytes that infiltrate into the tumor microenvironment in response to cytokines such as VEGF, colony stimulating factor-1 (CSF1), CXC motif chemokine ligand-12 (CXCL12) and various CC motif chemokine ligands (CCL) such as CCL2 [87,88][66][67]. TAMs make up about 10% of the BM of patients and have been found in higher proportions in patients with aggressive disease [89,90,91][68][69][70]. In vitro studies have recently shown that the IL10 secretion by MM cells polarized macrophages towards M2 phenotype and that inhibition of IL10 signaling with an IL10 receptor blocking antibody resulted in reversal of the M2 phenotype and loss of TAM-mediated MM proliferation and drug resistance [92][71]. Functionally, TAMs support MM proliferation (by secreting IL6), angiogenesis (by secreting VEGF, CCLs, matrix metalloproteinases (MMPs)), and immunosuppression (by secreting IL10, TGFβ, indoleamine 2,3-dioxygenase (IDO) and inhibiting IL12 and TNFα production) in the tumor microenvironment [93,94][72][73].
Other strategies to target TAMs in the MM BM microenvironment include (1) depleting TAMs by direct killing with clodronate-liposome or inhibiting chemokine signaling (e.g., CXCL12-CXCR4, CCL2-CCR2 to interrupt monocyte recruitment into the BM [95[74][75][76][77][78],96,97,98,99], (2) polarizing TAMs towards an M1 phenotype by inhibiting CSF1 receptor signaling or the pro-M2 cytokine macrophage migration inhibitory factor, or by using granulocyte-macrophage CSF (GM-CSF) or the Janus kinase (JAK) 1/2 inhibitor ruxolitinib, both of which have been shown to induce M1 polarization [100[79][80],101], and (3) inhibiting the immunosuppressive effects of TAMs [79][58]. To this end, research into inhibiting IDO to restore T-cell function is currently underway [46][25].

7. N2 Neutrophils

Owing to significant phenotypic and functional overlap between N2 neutrophils and PMN-MDSCs, there has been some confusion on the classification of these cells [102][81]. In fact, density gradient centrifugation is the only way to phenotypically differentiate TANs from PMN-MDSCs (which end up on the low-density layer) [103][82]. Unlike T and NK cells, the role of neutrophils in the tumor microenvironment is less clear as tumor-associated neutrophils have been found to possess both anti-tumor (e.g., direct cytotoxicity and inhibition of metastasis) and pro-tumor activity (e.g., promote angiogenesis, stimulate tumor cell migration and invasion, contribute to immunosuppression) [102][81]. Similar to TAMs, neutrophils maintain functional plasticity and can be alternatively activated in response to microenvironmental cues. Specifically, the presence of TGFβ within the microenvironment polarizes neutrophils towards a protumor phenotype (termed N2 neutrophils), while the presence of interferon-β (IFNβ) results in an antitumor phenotype (termed N1 neutrophils) [102][81].
Neutrophils isolated from the peripheral blood of patients with newly diagnosed MM have been shown to have a different gene expression profile compared with healthy donor-derived neutrophils [104][83]. Compared with both healthy donors and MGUS, neutrophils derived from patients with MM had genes dysregulated in FC-γ-R mediated phagocytosis, endocytosis, leukocyte transendothelial migration, chemokine signaling Toll-like receptor pathways, and inositol-phosphate metabolism [104][83]. Functionally, there is limited data showing that neutrophils derived from both the peripheral blood and BM of patients with MM were able to inhibit T-cell proliferation in a similar fashion to PMN-MDSCs by producing ROS and/or arginase-1 (which depletes L-arginine from the microenvironment) [104,105][83][84]. Noteworthy, studies present conflicting results with some showing that neutrophils derived from the peripheral blood of patients with MM did not have an increased T-cell inhibitory effect compared with peripheral blood neutrophils from healthy donors [105][84].

8. Regulatory B Cells (Bregs)

Bregs are a subset of B cells characterized by CD19+CD24highCD38high that, similar to Tregs, secrete IL10, IL35, and TGFβ and have been implicated in MM progression [106,107,108][85][86][87]. Bregs have been found to preferentially accumulate in the BM (as opposed to peripheral blood) of patients with MM [107][86]. Consistent with this, Bregs isolated from the BM of patients with MM were dependent on MM cells for survival in vitro as removal of CD138+ MM cells from the BM mononuclear cell culture resulted in Breg apoptosis as measured by the annexin V/propidium iodide apoptosis assay [107][86]. MM-derived Bregs were found to highly express TACI and the addition of APRIL in vitro increased the frequency of IL10-producing Bregs [50][29]. Functionally, a greater percentage of Bregs isolated from the BM were IL10 producing when compared to peripheral blood Bregs, and BM Bregs were able to inhibit elotuzumab associated antibody-dependent cellular cytotoxicity (ADCC) by NK cells [107][86].
Bregs also express PDL1 and CD1d on the cell surface, the latter of which is a nonpolymorphic MHC class I-like molecule found on antigen-presenting cells that facilitates the presentation of glycolipid antigens to natural killer T (NKT) cells, a process that is essential for the development of invariant NKT cells [106][85]. CD1d is also highly expressed by MM cells, especially during early stages of disease progression and MM cells can “hijack” this normally proinflammatory antigen presenting system to instead disrupt iNKT cell function [109][88]. MM cells secrete GM3 ganglioside, which together with the high levels of CD1d expression in the BM microenvironment, results in the formation of the CD1d/GM3 complex, which binds to the invariant T-cell receptor of iNKT resulting in iNKT deregulation, loss of IFNγ secretion, and immune evasion [109][88].

9. Impaired Immune Effector Killing in MM

The functional sequelae of the immunosuppressive BM microenvironment are diminished effector T-cell survival, proliferation, and function, evidenced by multiple CD4 and CD8 T-cell signaling defects (e.g., downregulation of CD28, CD152, CD3ζ, p56lck, ZAP-70, and PI3K; upregulation of exhaustion markers) in patients with advanced stage MM [110][89]. Additionally, the MM BM microenvironment is enriched for coinhibitory molecules (e.g., PDL1 on MM cells, Galectin-3 and HLA-DR on MM cells, Galectin-9 in the MM BM plasma; and corresponding immune checkpoint receptors PD1, LAG3, and TIM3 on T cells) [111,112,113,114,115,116,117,118][90][91][92][93][94][95][96][97]. Soluble factors such as IL6 (via JAK2/STAT3 and MEK/ERK signaling), IFNγ (via MyD88/TRAF6 and MEK/ERK signaling), and APRIL (via BCMA binding and MEK/ERK signaling) are found in high abundance within the MM BM microenvironment and have been implicated in promoting PDL1 expression [113,114,115,119][92][93][94][98]. In spite of this, clinical trials studying monotherapy with PD1/PDL1 inhibitors have yielded lackluster results, and this is likely due to the highly dysfunctional MM T cells, which coexpress T-cell immunoglobulin mucin-3 (TIM3) and lymphocyte-activation gene 3 (LAG3), and a combined blockade of multiple checkpoint pathways may be needed [116,117,120][95][96][99].

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