1-Methyl-D-tryptophan Reduces Tumor CD133+ cells, Wnt/\u03b2-catenin and NF-\u03ba\u03b2p65 while Enhances Lymphocytes NF-\u03ba\u03b22, STAT3, and STAT4 Pathways in Murine Pancreatic Adenocarcinoma

Murad Alahdal,Tingting Tang,Jin Liang,Yun Xing

doi:10.1038/s41598-018-28238-8

Murad Alahdal, Tingting Tang + Show 2 more

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https://doi.org/10.1038/s41598-018-28238-8

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Abstract

1-Methyl-D-tryptophan (1-MT) is extensively utilized in preclinical trials to deplete indoleamine 2,3-dioxigenase (IDO) activity and kynurenine pathway. Since IDO related signaling pathways aren’t well understood, some clinical reports affirmed IDO inhibiting therapeutic significance. Therefore, we did use direct tumor autologous antigens vaccination and 1-MT without chemotherapy to explore biological mechanisms and immunomodulations of 1-MT that motivate antitumor responses. However, DCs antigen-uptake capability, anti-tumor efficiency, intra-tumor and intracellular cytokines were assessed. Besides, CD133+ cells viability and tumor biomarkers were investigated. Splenocytes responses and their signaling pathways such TLRs 2 to 9, NF-κβ1-2, Wnt/β-catenin and TGF-β were dissected. Results evinced that a regimen of 1-MT and TAAs significantly reduced CSC CD133 + viability inside tumor microenvironment, besides increasing tumor cells necrosis and apoptosis. Expression of TGF-β, IDO, RANTES, and PDL-1 was also significantly reduced. Interestingly, 1-MT enhanced lymphocytes TLR2, TLR7, TLR8, and TLR9 pathways. It motivated lymphocytes’ NF-κβ2, STAT3, and STAT4 pathways, while reduced tumors’ NF-κβp65 and Wnt/β-catenin signaling pathways. We found that periphery and intra-tumor Treg cells were significantly decreased. In conclusion, depletion of indoleamine 2,3-dioxigenase activity evidenced IDO relation with tumor stem cells proliferation pathways. Furthermore, 1-MT supports immunotherapeutic vaccines susceptibility and tumor specific targeting by reducing tumorgensis signaling pathways.

Highlights

Projects consider IDO work motifs, which could explain clear working itinerary of IDO related pathways to help identification of critical therapeutic target
The analysis of dendritic cells (DCs) tumor antigens (TL) uptake potential showed that DCs significantly pulsed in response to tumor lysate in comparison to phosphate-buffered saline (PBS)
MHCII, CD40 and CD80 genes expression showed significant increasing in comparison to PBS (Fig. 1B); these findings suggested that DCs effectively recognized tumor antigens and efficiently presented to T cell

Summary

Introduction

Projects consider IDO work motifs, which could explain clear working itinerary of IDO related pathways to help identification of critical therapeutic target. It promotes different signaling pathways to suppress T-cell responses, and enhancing Treg cells[15,16] Collecting all these details together, we find that IDO knockout or inhibition without chemotherapy applications could represent IDO biological signaling pathways in tumor cells and lymphocytes. IDO relation with immune cells is complicated and needs deep understanding. It mainly produced from Mesenchymal stromal cells, endothelial cells, fibroblasts, and myeloid-derived antigen-presenting cells[17,18]. We blocked IDO activity by using 1-Methyl-D-tryptophan, and used a biological vaccine (tumor autologous antigens) to explore clear evidences regarding virtual work mechanisms and pathways ascribed to IDO activity, without chemotherapy that could confuse results interpretation, because of its harmful side effects[26]. We considered pancreatic adenocarcinoma model in the mice, because recently it’s one of the most aggressive cancers in the world, which showed high rates of IDO overexpression associated tumor aggressiveness[27,28]

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