1-Methyl-D-tryptophan Reduces Tumor CD133+ cells, Wnt/?-catenin and NF-??p65 while Enhances Lymphocytes NF-??2, STAT3, and STAT4 Pathways in Murine Pancreatic Adenocarcinoma.

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-??1-2, Wnt/?-catenin and TGF-? 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-?, IDO, RANTES, and PDL-1 was also significantly reduced. Interestingly, 1-MT enhanced lymphocytes TLR2, TLR7, TLR8, and TLR9 pathways. It motivated lymphocytes' NF-??2, STAT3, and STAT4 pathways, while reduced tumors' NF-??p65 and Wnt/?-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.

SUBMITTER: Alahdal M 

PROVIDER: S-EPMC6026162 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature