Table 2 Comprehensive overview of treatments in neuroblastoma removing myeloid cells from the tumor microenvironment
From: Targeting the myeloid microenvironment in neuroblastoma
Therapeutic target | Treatment | Treatment strategy | Studied population | Pre-clinical model | Outcome | Ref |
|---|---|---|---|---|---|---|
CD11b | Anti-CD11b | Depletion | Myeloid lineage | NXS2 xenograft model | Tumor growth delay, prolonged survival | [164] |
CD105 | Anti-CD105 | Depletion | Monocytes, MSC, endothelial cells | PDX models | Improved efficacy of anti-GD2 antibodies when combined with adoptively transferred activated human NK cells | [165] |
Ly6G | Anti-Ly6G (+ GD2-EATs) | Depletion | PMN, PMN-MDSC | PDX models | Higher T cell and M-MDSC infiltration in the tumor, prolonged survival | [166] |
Ly6C | Anti-Ly6C (+ GD2-EATs) | Depletion | Monocytes, M-MDSC | PDX models | Decrease in TAM and increase in intratumoral PMN-MDSC and T cells, prolonged survival | [166] |
Macrophages/CSF1R | Clodronate liposomes or anti-CSF-1R (+ GD2-EATs) | Depletion | TAM | PDX models | Decrease in M-MDSC and increase in PMN-MDSC and T cells, prolonged survival | [166] |
CSF1R | Inhibitor BLZ945 + anti-CSF-1R | Depletion | Monocytes, TAM | CHLA-136 and CHLA-255 xenograft and PDX models | Improvement of chemotherapeutic efficacy, which was independent of T cell contribution | [167] |
CSF-1 | Small interfering RNAs | Depletion | TAM | SK-N-AS and SK-N-DZ xenograft models | Decreased intratumoral TAM, matrix metalloprotease 12 levels and angiogenesis, suppression of tumor outgrowth | [168] |
Glucocorticoid receptor | Dexamethason (+ GD2-EATs) | Depletion and reprogramming | Monocytes, TAM, M-MDSC | PDX models | Decrease in IL-2, IL-6, and TNF-α release, increase in PMN-MDSC and T cells, and enhanced survival | [166] |
CD33 | Gemtuzumab ozogamicin | Depletion | MDSC | In vitro | Restored T cell proliferation, MDSC cell death, enhanced anti-GD2 CAR-T cell activity | [169] |
CD1d/GM-CSF | NKT cells | Depletion and reprogramming | MDSC, TAM | In vitro, CHLA-255 xenograft model | Killing of suppressive TAM and MDSC via CD1d, NKT cells-derived GM-CSF differentiates TAM to M1, decrease of IL-10 expression in PMN-MDSC | |
Apoptosis (via ROS) | Doxorubicin | Depletion and reprogramming | MDSC | In vitro, Neuro2a syngeneic model | Increased T cell proliferation and function, reduction in Tregs, less suppressive myeloid cells, inhibition of TAM polarization to M2, improved efficacy of anti-GD2 and adoptive T cell transfer, improved survival | |
Apoptosis (via ROS) | Doxorubicin | Depletion | MDSC | In vitro | improved antigen-specific CTL-killing, via upregulating CD3ζ and L-selectin | [175] |
Forming DNA adducts | Cisplatin | Depletion | M-MDSC | SK-N-DX xenograft model | Reducing tumor burden | [176] |
Thymidylate synthase | 5-FU | Depletion | MDSC | Syngeneic mouse model | Reduction of CD11b + cells in the tumor, improved efficacy of anti-GD2 | [164] |
Thymidylate synthase | 5-FU | Depletion | MDSC | Neuro2A-bearing chimeras | Improved local tumor growth-inhibitory effect of recipient leukocyte infusion | [177] |
STAT3 | AZD1480, ruxolitinib | Inhibition of cytokines | TAM | NBT2 model in NB-TAG and NSG mice | Reduction of TAM-mediated upregulation of MYCN tumor growth inhibition | [88] |
STAT3 | STAT3 inhibition, or knockdown | Inhibition of cytokines | TAM | In vitro | Abrogates drug-resistance to etoposide and melphalan due to monocyte-derived IL-6 inducing STAT3 signaling | [178] |
IL-6R | Tocilizumab | Inhibition of cytokines | TAM | CHLA-255 and CHLA-136 xenograft models | Apoptosis of TAM | [95] |
TGF-βR1 | Galunisertib | Inhibition of cytokines | TAM, MSC | CHLA-255 and CHLA-136 xenograft models | Decrease of IL-6 production by NB cells, apoptosis of TAM, restored NK cell activity | [95] |
TGF-β | Anti-TGF-β | Blocking recruitment | TAM | TH-MYCN mice | Decreased recruitment of M2 TAM | [179] |
COX enzymes | Aspirin | Blocking recruitment | MDSC, immature DC, TAM | TH-MYCN mice | Decreased recruitment of MDSCs, immature DCs and TAMs, reduced tumor burden | |
CXCR2 | Anti-CXCR2 | Blocking recruitment | TAM, CAF | In vitro | Abrogation of the invasive ability of NB cells induced by TAM-derived CXCL2 | [73] |
CCL2 | S1P2 agonist AB1 and JTE-013 | Blocking recruitment | TAM | SK-N-AS xenograft model | Inhibition of TAM infiltration, reduced VEGF expression and reduced tumor outgrowth | |
DNA synthesis | Oxaliplatin | Blocking recruitment | PMN | TH-MYCN mice | Low-dose decreases recruitment PMN | [179] |