Tumor-associated Schwann cells Expressing LncRNAs Direct Immune Resistant Metabolic Microenvironment
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ABSTRACT: One of the major obstacles of treating pancreatic ductal adenocarcinoma (PDAC) is the immune-resistant microenvironment, by which the mechanisms remains elusive. We demonstrated that tumor-associated Schwann cells (TAScs) play important roles in promoting an immune-resistant microenvironment. The abundance of TASc is correlated with the expression of negative immune checkpoints and infiltration of tumor-promoting immune cells. TASc-expressed Plasmacytoma Variant Translocation 1 (PVT1) is triggered by the tumor cell-produced Interleukin-6 (IL-6). Mechanistically, PVT1 modulates the RAF proto-oncogene serine/threonine-protein kinase (RAF1)-mediated phosphorylation of Tryptophan 2,3-dioxygenase (TDO2) in TASc, facilitating the enzymatic activities of TDO2 in catalyzing Tryptophan (Trp) to Kynurenine (Kyn). The release of Kyn in the microenvironment further modulates colony-stimulating factor 1 (CSF1) signaling, leading to the expansion of Myeloid-derived suppressor cells (MDSCs) and diminished infiltration of effector T-cells. Depletion of TASc-expressed PVT1 or TASc using small molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.
ORGANISM(S): Mus musculus
PROVIDER: GSE171557 | GEO | 2021/12/08
REPOSITORIES: GEO
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