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

Abstract

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.

Pancreatic Schwann cell reprogramming supports cancer-associated neuronal remodeling

“…The abovementioned activities of SCs position them as potential candidates for directing neuronal remodeling during cancer development; this is in line with the presence of nonmyelinating SCs in the PDAC tumor microenvironment and around non-invasive PanIN precursor lesions Demir et al, 2014;Sun et al, 2023;Xue et al, 2023).…”

“…The abovementioned activities of SCs position them as potential candidates for directing neuronal remodeling during cancer development; this is in line with the presence of non-myelinating SCs in the PDAC tumor microenvironment and around non-invasive PanIN precursor lesions (Deborde et al, 2022; Demir et al, 2014; Sun et al, 2023; Xue et al, 2023). Cancer cells can induce phenotypic reprogramming of SCs, resembling injury-induced repair SCs (Deborde et al, 2016; Shurin et al, 2019).…”

“…SCs have been implicated in promoting tumor growth and facilitating the metastatic dissemination of cancer cells through invading peripheral nerves (Deborde et al, 2022, 2016; Demir et al, 2014, 2017, 2016; Shurin et al, 2019; Sun et al, 2023; Weitz et al, 2023; Xue et al, 2023). These roles mainly result from the direct interactions between SCs and cancer cells and do not involve neurons.…”

A Review of the Evidence for Tryptophan and the Kynurenine Pathway as a Regulator of Stem Cell Niches in Health and Disease

“…TDO2 has also been implicated in the production of an immunosuppressed environment that promotes cancer cell survival. 60 , 353 - 355 Its overexpression is correlated with tumour grade and poor prognosis in triple-negative breast cancer and brain tumours, with TDO2 inhibition suggested as a therapeutic target in oesophageal cancer. 353 Upregulation of other downstream KP enzymes including AFMID, 356 KMO, 357 - 360 KYNU 361 and QPRT, 362 - 364 has also been observed in various cancers.…”

The Expanding Roles of Long Non‐Coding RNAs in Pancreatic Cancer

“…Depletion of TASc-expressing lncRNA PVT1 restored the immuneresistant tumor microenvironment and improved the antitumor effects of immune checkpoint inhibitors. [108] Decreased or increased lncRNA levels may lead to functional changes in immune cells. LncRNAs can regulate immune cell function by regulating the differentiation, proliferation, migration, and apoptosis of immune cells, thereby affecting their ability to kill tumor cells.…”