Table 3 Comprehensive overview of treatments in neuroblastoma reprogramming myeloid cells into an immunostimulatory phenotype
From: Targeting the myeloid microenvironment in neuroblastoma
Therapeutic target | Treatment | Studied population | Pre-clinical model | Outcome | Ref |
|---|---|---|---|---|---|
BTK | Ibrutinib | MDSC | 9464D syngeneic model | Decrease of NO expression and of Ido, Arg, and Tgfb mRNA expression in MDSC, reversion of T cell suppression, increased CD8+ T cell infiltration, improved response to anti-PD-L1 | [193] |
CSF1R (and PD1) | BLZ945 (+ anti-PD-1) | MDSC, monocytes | TH-MYCN mice | Reverted suppressive functions of tumor-educated monocytes, abolished induction of MDSC, activation of tumor-reactive T cells, improved anti-PD-1/PD-L1 blockade | |
TLR2 | NAP (+ CAR T cells or oncolytic virus) | PMN | NXS2 syngeneic model | infiltration of neutrophils, M1 macrophages, NK cells, CD8+ T cells and DCs, reduced number of Tregs, reduced tumor growth | |
mPGES-1 | Small molecule inhibitor | CAFs, TAM | SK-N-AS xenograft model and TH-MYCN mice | PGE2 production was inhibited by CAFs, resulting in reduced tumor growth, impaired angiogenesis, and polarization of TAM to pro-inflammatory M1 | [199] |
Histone deacetylation | Vorinostat (+ retinoic acid or MIBG) | TAM, M-MDSC | TH-MYCN mice, phase I clinical trial | Upregulation of GD2 in NB cells, increase of TAM with mixed M1 and M2 phenotype, depletion of M-MDSC, downregulation of suppressive markers on myeloid cells, beneficial response rates in NB patients | |
IFNγ | IFNγ-expressing MSC | TAM | CHLA-255 orthotopic xenograft model | TAM polarization to M1 phenotype, reduced tumor growth, prolonged survival | [203] |
FABP4 | Anti-IL-1a | TAM | In vitro | Suppression of FABP4-mediated migration and invasion of NB cells | [204] |
CD40 | CD40 agonist | TAM | NXS2 syngeneic model | M1 polarization of TAMs | [205] |
CD40 | CD40 agonist + CpG | TAM | NXS2 syngeneic model | Anti-CD40 primes TAM to respond to CpG, resulting in M1 polarization and tumor growth inhibition | [206] |
CD40 | CD40 agonist + CpG + chemo, or radiation, anti-GD2 and anti-CTLA-4 | TAM | 9464D syngeneic model | Synergistic anti-tumor effects of combination treatments via repolarization of TAMs to M1 phenotype | |
Rac2 | Rac2 knockout | TAM | Rac2−/− mice with 9464D model | Rac2 knockout promotes M1 TAM differentiation, reduced tumor growth | [208] |
67 kDa laminin receptor | Polyphenon E | MDSC, PMN | TH-MYCN mice | Impairment of development and motility of MDSC, MDSC differentiation towards PMN, induction of G-CSF, decreased Arg-1 expression on remaining MDSC, increased T cell proliferation | [65] |
BRD3/4 | BET bromodomain inhibitors | Myeloid cells | In vitro, multiple in vivo models | Tumor growth inhibition, MYCN downregulation, possibly reprogramming of myeloid cells |