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胱抑素A在小鼠胰腺癌模型中促进1型辅助性T细胞和树突状细胞的抗肿瘤活性。

Cystatin A promotes the antitumor activity of T helper type 1 cells and dendritic cells in murine models of pancreatic cancer.

作者信息

Nasti Alessandro, Inagaki Shingo, Ho Tuyen Thuy Bich, Seki Akihiro, Yoshida Keiko, Satomura Kosuke, Sakai Yoshio, Kaneko Shuichi, Yamashita Taro

机构信息

Information-Based Medicine Development, Graduate School of Medical Sciences, Kanazawa University, Japan.

System Biology, Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Japan.

出版信息

Mol Oncol. 2025 May;19(5):1452-1470. doi: 10.1002/1878-0261.13796. Epub 2025 Jan 10.

DOI:10.1002/1878-0261.13796
PMID:39792573
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12077287/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a disease with poor prognosis due to diagnostic and therapeutic limitations. We previously identified cystatin A (CSTA) as a PDAC biomarker and have conducted the present study to investigate the antitumor effects of CSTA. PDAC murine models were established with genetically modified PAN02 tumor cell lines to evaluate the antitumor immune response. PDAC mouse survival was significantly longer with CSTA, and its antitumor effect was mediated mainly by CD4+ cells and partly by CD8+ cells. We also observed an increased infiltration of CD4+ and CD8+ cells in tumors of mice overexpressing CSTA. Phenotypically, we confirmed higher T helper type 1 (Th1) cell activity and increased frequency and activity of M1 macrophages and dendritic cells (DCs) in CSTA-overexpressing mice. Gene expression analysis highlighted pathways related to interferon gamma (IFN-γ) induction and Th1 lymphocyte activation that were induced by CSTA. Macrophages and DCs shifted toward proinflammatory antitumor phenotypes. Furthermore, activated splenocytes of PDAC model mice expressing CSTA had increased proapoptotic activity. CSTA also promoted the selective migration of CD4+ and CD11c+ immune cells in an in vitro migration assay. In conclusion, CSTA exerts antitumor effects by enhancing Th1-mediated antitumor effects through promotion of DC and M1 macrophage activity, thereby increasing immune cell chemotaxis. CSTA could be a novel therapeutic candidate for PDAC.

摘要

胰腺导管腺癌（PDAC）是一种由于诊断和治疗局限性而预后较差的疾病。我们之前将胱抑素A（CSTA）鉴定为一种PDAC生物标志物，并开展了本研究来探究CSTA的抗肿瘤作用。利用基因改造的PAN02肿瘤细胞系建立了PDAC小鼠模型，以评估抗肿瘤免疫反应。使用CSTA后，PDAC小鼠的生存期显著延长，其抗肿瘤作用主要由CD4+细胞介导，部分由CD8+细胞介导。我们还观察到，在过表达CSTA的小鼠肿瘤中，CD4+和CD8+细胞的浸润增加。从表型上看，我们证实过表达CSTA的小鼠中1型辅助性T细胞（Th1）活性更高，M1巨噬细胞和树突状细胞（DCs）的频率和活性增加。基因表达分析突出了与干扰素γ（IFN-γ）诱导和Th1淋巴细胞活化相关的通路，这些通路由CSTA诱导。巨噬细胞和DCs向促炎性抗肿瘤表型转变。此外，表达CSTA的PDAC模型小鼠的活化脾细胞具有增强的促凋亡活性。在体外迁移试验中，CSTA还促进了CD4+和CD11c+免疫细胞的选择性迁移。总之，CSTA通过促进DC和M1巨噬细胞活性来增强Th1介导的抗肿瘤作用，从而增加免疫细胞趋化性，发挥抗肿瘤作用。CSTA可能是一种用于PDAC的新型治疗候选药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/42b18a42e1c8/MOL2-19-1452-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/da33010f373f/MOL2-19-1452-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/2fc10cedfbd3/MOL2-19-1452-g003.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/bed3df1d31c5/MOL2-19-1452-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/f3ec6685c4c1/MOL2-19-1452-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/42b18a42e1c8/MOL2-19-1452-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/da33010f373f/MOL2-19-1452-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/2fc10cedfbd3/MOL2-19-1452-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/243440bcd821/MOL2-19-1452-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/bed3df1d31c5/MOL2-19-1452-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/47ab/12077287/42b18a42e1c8/MOL2-19-1452-g002.jpg

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本文引用的文献

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Correlated with better prognosis, CSTA inhibits metastasis of nasopharyngeal carcinoma cells via suppressing AKT signaling through promoting METTL3 degradation.与更好的预后相关，CSTA 通过促进 METTL3 降解来抑制 AKT 信号通路从而抑制鼻咽癌细胞的转移。
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Microglia drive transient insult-induced brain injury by chemotactic recruitment of CD8 T lymphocytes.
小胶质细胞通过趋化性招募 CD8+T 淋巴细胞来驱动短暂性损伤诱导的脑损伤。
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