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肿瘤相关非髓鞘 Schwann 细胞表达的 促进胰腺癌犬尿氨酸途径和肿瘤免疫排斥。

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

机构信息

Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA.

出版信息

Sci Adv. 2023 Feb 3;9(5):eadd6995. doi: 10.1126/sciadv.add6995. Epub 2023 Feb 1.

DOI:10.1126/sciadv.add6995
PMID:36724291
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9891701/
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 () was triggered by the tumor cell-produced interleukin-6. Mechanistically, 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 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.

摘要

治疗胰腺导管腺癌 (PDAC) 的主要障碍之一是其免疫抵抗微环境。施万细胞在 PDAC 中的功能重要性和分子机制在很大程度上仍未被揭示。我们对 PDAC 中的肿瘤相关非髓鞘施万细胞 (TASc) 的基因特征进行了表征，并表明 TASc 的丰度与免疫抑制性肿瘤微环境以及 PDAC 患者的不良预后相关。胰腺特异性 TASc 的耗竭促进了 PDAC 肿瘤的发生。TASc 表达的长非编码 RNA (lncRNA) 浆细胞瘤变异易位 1 () 是由肿瘤细胞产生的白细胞介素-6 触发的。在机制上， 调节 RAF 原癌基因丝氨酸/苏氨酸蛋白激酶介导的 TASc 中色氨酸 2,3-加双氧酶的磷酸化，促进其在催化色氨酸生成犬尿氨酸中的酶活性。TASc 表达的 的耗竭抑制了 PDAC 肿瘤的生长。此外，使用小分子抑制剂耗竭 TASc 可有效增强 PDAC 对免疫治疗的敏感性，表明 TASc 在 PDAC 免疫抵抗中的重要作用。

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