Table 2.
Overview of MDSC-targeting approaches in hematological cancers.
| Agents | Disease | Model | Mechanisms/ Functions | Ref | |
|---|---|---|---|---|---|
| Cytotoxic therapies | 5-FU | Lymphoma | EL-4 syngeneic model | Gemcitabine and 5-FU decreased the number of MDSC. | (58) |
|
Gemcitabine |
MM Lymphoma |
5T33MM model A20 syngeneic model E.G7-OVA model |
Targeting MDSC by anti-GR1 antibodies and 5-FU reduced tumor load. Accumulation of MDSC in the spleen of lymphoma-bearing mice. Lipid nanocapsules loaded with a lauroyl-modified form of gemcitabine efficiently target the M-MDSC subset. |
(59) (60, 61) | |
| Monoclonal antibodies | Daratumumab | MM | Patient PB, BM samples | G-MDSC expressed elevated CD38 and were highly sensitive to daratumumab-mediated ADCC/CDC. Daratumumab-mediated depletion of M-MDSC using a combination of daratumumab and cetrelimab in RRMM patients. |
(62) (63) |
| MDSC-depleting peptibodies | Peptibodies | Lymphoma | EL-4 syngeneic model | In vivo, intravenous peptibodies injection depleted blood, splenic and intra- tumoral MDSC. S100 family proteins were identified as candidate targets. | (64) |
| Brentuximab Vedotin | HL | Patient PB samples | BV reduced the absolute number of three MDSC subtypes and s-Arg-1 levels. Patients with baseline s-Arg-1 >200 ng/ml had inferior PFS at 36 months. | (65) | |
| Epigenetic compounds | Decitabine | Lymphoma Leukemia MM |
EL-4 syngeneic model WEHI-3 model MPC-11 model |
DAC treatment depleted MDSC in vivo. DAC activated adaptive T-cell response in vitro and autologous T-cell response to tumor cells in vivo by depleting MDSC. | (66) |
| DAC treatment inhibited MPC-11 proliferation in vivo by depleting M-MDSC and increasing T-cell infiltration in tumor tissue. | (67) | ||||
| ACY241 | MM | Patient BM samples | ACY241 decreases the frequency and expression of immune checkpoints on CD138+ MM cells, regulatory T-cells and MDSC. | (68) | |
| CD33/CD3-bispecific BITE® antibody | AMG330 | Leukemia | Primary AML-blasts | AMG330 triggers T-cell mediated lysis of AML-blasts that is further enhanced by MDSC depletion. | (69) |
| AMV564 | MDS | MDS BM primary samples, CD33hi SKM1 xenograft model | AMV 564 showed anti-tumor activity by immunodepletion of MDSC in primary MDS patients and in a disseminated leukemia mouse model. | (70) | |
| LXR agonist RGX- 104 | RGX-104 | Lymphoma | LXR agonist treatment promotes MDSC apoptosis in vitro and in vivo. Patient blood sample analysis revealed a depletion of G-MDSC after treatment of cancer patients with RGX-104. | (71) | |
| Immunomodulatory drugs | Lenalidomide Pomalidomide | MM | Patient PB, BM samples | LEN and POM prevent MDSC induction through transcriptional expression and production of CCL5 and MIF, and increased the mRNA level of IRF8 (a negative regulator of differentiation towards MDSC) in PBMC. | (72) |
| Immune checkpoint inhibitors | VISTA- targeting | AML | Patient PB samples C1498 syngeneic PD-1H knockout model | VISTA is highly expressed on MDSC in patients, and increased in ND patients. VISTA knockout/targeting diminished the inhibition of CD8 T-cell activity by MDSC in AML. VISTA on host cells and AML cells induces immune evasion in AML. | (73, 74) |
| Tyrosine kinase inhibitors | Ibrutinib | CLL | A cohort of previously untreated CLL patients, PBMC samples | Ibrutinib therapy selectively alters the numbers of MDSC, CD4+ and CD8+ T-cells and Th-cell subsets in vivo. | (32) |
| Dasatinib | CML | Patients and age-matched HD PB samples | The percentage of M-MDSC correlates with MMR in patients treated with dasatinib. | (75, 76) | |
| Metabolic Reprogramming Immunosurveillance Activation Nanomedicine | MRIAN | T-ALL | Activated Notchl mutant driven T-ALL model | MRIAN efficiently penetrates BM and selectively targets leukemic cells and MDSC in T-ALL mice. MRIAN Inhibits mitochondrial metabolism and reduces ROS levels in MDSC. | (77) |
| Notch inhibitors | ADAM10 Anti-Jagged antibody |
T-ALL Lymphoma |
ADAM10 transgenic (A10Tg) model Patient PB samples Notch3-transgenic T-ALL model Notchl-activated KE-37 cell line and HD PB EL-4 syngeneic model |
ADAM10 overexpression in transgenic mice resulted in a systemic expansion of MDSC. The accumulation of MDSC was attributed to the differential cleavage of Notch in S2 and S3 products by ADAM10. Daratumumab-mediated depletion of M-MDSC using a combination of daratumumab and cetrelimab in RRMM patients Notch-signaling deregulation in immature T-cells promotes CD11b+Grl+ MDSC in the Notch3-transgenic murine model of T-ALL. Human Notch-Dependent T-ALL cell lines induce MDSC from HD PBMC. Tumors induce Jagged ligands in MDSC through NFκB-p65. Anti-Jagged therapy induces an anti-tumor effect, and impacts the suppressive activity of tumor-MDSC. |
(78–80) |
| S100A9 inhibitors | ABR-238901 | MM | 5T33MM model | Blocking S100A9 interactions with ABR-238901 did not directly affect MDSC accumulation but did reduce IL-6 and IL-10 expression by MDSC. ABR-238901 treatment in combination with bortezomib resulted in an increased reduction in tumor load compared with single treatments. | (81) |
| Tasquinimod | 5T33MM model 5TGM1 model | Tasquinimod has direct anti-tumor effects in vivo. Tasquinimod targets M-MDSC and increases serum interferon-gamma. | (82) | ||
| STAT3 inhibitors | AZD9150 | NHL (primarily DLBCL) | Patient PB | AZD9150 therapy resulted in a decrease of G-MDSC and increased CD4 and CD8 T-cells in three out of four NHL patients. | (83) |
| Phosphodiesterase-5 inhibitors | Sildenafil | B cell lymphoma | A20 syngeneic model | IL-4Ra expression on MDSC correlates with tumor progression and can be inhibited by sildenafil. | (84) |
| Tadalafil | MM | Case report MM patient | Tadalafil, in a patient with end-stage RRMM reduced MDSC function and generated a dramatic and durable anti-myeloma immune and clinical response. | (85) | |
| Clinical trial of MM patients (refractory to lenalidomide-based regimens | MDSC were not detected in any of the patients at baseline in both blood and BM. No clinical response could be observed. | (86) | |||
| NOX2 inhibitor | Histamine hydrochloride | Lymphoma | EL-4 syngeneic model | HDC reduces tumor progression by targeting NOX2+ MDSC. HDC significantly reduced the accumulation of MDSC within EL-4 lymphomas. | (87) |
| Arginase inhibitor | nor-NOHA CD1158 | MM | Patient PB samples | T-cell proliferation and cell cytotoxicity is enhanced by PMN-SN in the presence of arginase inhibition. T-cell cytokine secretion is hyperactivated by PMN-SN in the presence of arginase inhibition. | (16, 88) |
| AML | AML mice NOG-SCID mice | The AML mice had significant reductions in plasma arginine compared to controls. The arginine depleting therapy can inhibit antigen-dependent T cell responses in vitro and in vivo. | (89) | ||
| All-trans-retinoic acid | Lymphoma | EL-4 Syngeneic model | ATRA induces expression of GSS and accumulation of GSH in MDSC. | (90) | |
| APL | Transgenic PML-RARA APL model T-cell depletion in APL B6 model HIS APL model | In PML-RARA mice, the remission following ATRA treatment was accompanied with normalized levels of PGD2, ILC2s, M-MDSC, and a recovery of activated CD8+ T-cells. T-cell depleted APL B6 mice showed a shorter survival and an increase in ILC2 and M-MDSC. The increase in PGD2 and a major accumulation of ILC2 and M-MDSC upon leukemia engraftment were observed in HIS APL mice that were reverted by ATRA therapy. | (91) | ||
| PalmitoyItransferase inhibitor | 2-BP | AML | Patient PB samples | Palmitoylated proteins on the AML-EVs' surface contribute to the TLR2-dependent MDSC reprogramming | (92) |
5-FU, 5-fluorouracil; BV, brentuximab vedotin; DAC, decitabine; LEN, lenalidomide; POM, pomalidomide; VISTA/PD-1H, v-domain immunoglobulin suppressor of T-cell activation; MRIAN, metabolic reprogramming immunosurveillance activation nanomedicine; S100A9, calgranulin B or myeloid-related protein 14, MRP14; LXR, activation of liver X receptor; ADAM10, a disintegrin and metalloprotease 10; HDC, histamine hydrochloride; PMN-SN, polymorphonuclear neutrophil granulocytes supernatants; ATRA, all-trans-retinoic acid; MDS, myelodysplastic syndromes; T-ALL, T‐cell acute lymphoblastic leukemia; APL, acute promyelocytic leukemia; HIS, humanized mice; ADCC/CDC, Fc-mediated antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity; CCL5, C-C Motif Chemokine Ligand 5; MIF, macrophage migration inhibitory factor; IFR8, interferon regulatory factor 8; ROS, reactive oxygen species; NFκB-p65, nuclear factor kappa-light-chain-enhancer of activated B cells; IL6, interleukin 6; CTLs, cytotoxic T lymphocyte; GSS, glutathione synthase; GSH, glutathione; PDG2, a receptor for prostaglandin D2; ILC2, group 2 innate lymphoid cells.