Polyphenol E Enhances the Antitumor Immune Response in Neuroblastoma by Inactivating Myeloid Suppressor Cells

Abstract

Purpose: Neuroblastoma is a rare childhood cancer whose high risk, metastatic form has a dismal outcome in spite of aggressive therapeutic interventions. The toxicity of drug treatments is a major problem in this pediatric setting. In this study, we investigated whether Polyphenon E, a clinical grade mixture of green tea catechins under evaluation in multiple clinical cancer trials run by the National Cancer Institute (Bethesda, MD), has anticancer activity in mouse models of neuroblastoma.Experimental Design: We used three neuroblastoma models: (i) transgenic TH-MYCN mouse developing spontaneous neuroblastomas; (ii) nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice xenotransplanted with human SHSY5Y cells; and (iii) A/J mice transplanted with syngeneic Neuro 2A cells. Mice were randomized in control and Polyphenon E-drinking groups. Blood from patients with neuroblastoma and normal controls was used to assess the phenotype and function of myeloid cells.Results: Polyphenon E reduced the number of tumor-infiltrating myeloid cells, and inhibited the development of spontaneous neuroblastomas in TH-MYCN transgenic mice. In therapeutic models of neuroblastoma in A/J, but not in immunodeficient NOD/SCID mice, Polyphenon E inhibited tumor growth by acting on myeloid-derived suppressor cells (MDSC) and CD8 T cells. In vitro, Polyphenon E impaired the development and motility of MDSCs and promoted differentiation to more neutrophilic forms through the 67 kDa laminin receptor signaling and induction of granulocyte colony-stimulating factor. The proliferation of T cells infiltrating a patient metastasis was reactivated by Polyphenon E.Conclusions: These findings suggest that the neuroblastoma-promoting activity of MDSCs can be manipulated pharmacologically in vivo and that green tea catechins operate, at least in part, through this mechanism.

COX/mPGES-1/PGE 2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

“…This immunosuppressive state has been shown in human tumor samples by the infiltration of M2-polarized macrophages (23) and in neuroblastoma mouse models by the infiltration of MDSCs (26,36). Our data show predominance toward M2-polarization of the tumor-infiltrating macrophages (i.e., tumor-associated macrophages) in both 11q-deleted tumors and MYCN-amplified tumors, with elevated levels of CD206 and CD163, respectively (Fig.…”

Bioactive compounds or metabolites from black raspberries modulate T lymphocyte proliferation, myeloid cell differentiation and Jak/STAT signaling

“…A limited number of targeted, small molecule inhibitors, including sunitinib can also reduce MDSC expansion [42]. Of all the studies examining the use of natural products for cancer, only 25-hydroxyvitamin D3, curcumin, Withaferin A and Polyphenol E (green tea catechins) have been investigated as a means to modulate MDSC and resulting immune responses [23,25,24,26]. These data suggest that dietary products may serve as novel sources of compounds that can be used to modulate phenotypic and functional properties of the immune system.…”

Chemoprevention Against Arsenic-Induced Mutagenic DNA Breakage and Apoptotic Liver Damage in Rat Via Antioxidant and SOD1 Upregulation by Green Tea (Camellia sinensis) which Recovers Broken DNA Resulted from Arsenic-H2O2Related in Vitro Oxidant Stress

“…Green tea polyphenols show antioxidant and anticancer effects [16]. In the present study, we investigate and present for the first time the therapeutic role of Camellia sinensis (green tea) and its possible mechanism against arsenic-induced oxidative stress, mutagenic DNA breakage, and hepatic damage in rat and in vitro/in situ experimental model.…”