Tumor-associated nonmyelinating Schwann cell–expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion

Menée à l'aide de modèles murins et d'échantillons tumoraux issus de patients atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel le long ARN non codant PVT1, exprimé par les cellules de Schwann non-myélinisantes associées à la tumeur, favorise la croissance tumorale via la voie de transformation du tryptophane en kynurénine

Résumé en anglais

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell–produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase–mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance. Targeting tumor-associated non-myelinating Schwann cells improves response of immunotherapy-refractory pancreatic cancer.