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TLR9 单药疗法抑制免疫功能正常小鼠的原位前列腺肿瘤发展。

TLR9 Monotherapy in Immune-Competent Mice Suppresses Orthotopic Prostate Tumor Development.

机构信息

Centre for Respiratory Science and Health, School of Health and Biomedical Sciences, RMIT University, Bundoora, VIC 3083, Australia.

Infection and Immunity Program, Biomedicine Discovery Institute, Department of Pharmacology, Monash University, Clayton, VIC 3800, Australia.

出版信息

Cells. 2024 Jan 2;13(1):97. doi: 10.3390/cells13010097.

DOI:10.3390/cells13010097
PMID:38201300
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10778079/
Abstract

Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to both the progression and inhibition of prostate tumorigenesis. To further understand this apparent disparity, we have investigated the effect of TLR9 stimulation on prostate cancer progression in an immune-competent, syngeneic orthotopic mouse model of prostate cancer. Here, we utilized the class B synthetic agonist CPG-1668 to provoke a TLR9-mediated systemic immune response and demonstrate a significant impairment of prostate tumorigenesis. Untreated tumors contained a high abundance of immune-cell infiltrates. However, pharmacological activation of TLR9 resulted in smaller tumors containing significantly fewer M1 macrophages and T cells. TLR9 stimulation of tumor cells had no effect on cell viability or its downstream transcriptional targets, whereas stimulation in macrophages suppressed cancer cell growth via type I IFN. This suggests that the antitumorigenic effects of CPG-1668 were predominantly mediated by an antitumor immune response. This study demonstrated that systemic TLR9 stimulation negatively regulates prostate cancer tumorigenesis and highlights TLR9 agonists as a useful therapeutic for the treatment of prostate cancer.

摘要

前列腺癌在男性癌症相关死亡中排名世界第二，这突显了晚期疾病缺乏有效治疗方法的问题。Toll 样受体 (TLR) 和免疫在前列腺癌发病机制中具有直接作用，但 TLR9 被报道既促进前列腺肿瘤的进展，又抑制其发生。为了进一步了解这种明显的差异，我们在具有免疫能力的同种异体前列腺癌原位小鼠模型中研究了 TLR9 刺激对前列腺癌进展的影响。在这里，我们利用 B 类合成激动剂 CPG-1668 引发 TLR9 介导的全身免疫反应，并证明其对前列腺肿瘤发生有明显的抑制作用。未经治疗的肿瘤含有大量免疫细胞浸润。然而，TLR9 的药理学激活导致肿瘤更小，其中 M1 巨噬细胞和 T 细胞明显减少。TLR9 刺激肿瘤细胞对细胞活力或其下游转录靶标没有影响，而刺激巨噬细胞则通过 I 型干扰素抑制癌细胞生长。这表明 CPG-1668 的抗肿瘤作用主要是通过抗肿瘤免疫反应介导的。本研究表明，全身 TLR9 刺激可负向调节前列腺癌肿瘤发生，并强调 TLR9 激动剂是治疗前列腺癌的一种有用疗法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/def58f6208fa/cells-13-00097-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/f27afc7dabc3/cells-13-00097-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ab608398718a/cells-13-00097-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ad395f2290f9/cells-13-00097-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/2de31ffc1587/cells-13-00097-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ab92583880c8/cells-13-00097-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/d25ac6374f51/cells-13-00097-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/def58f6208fa/cells-13-00097-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/f27afc7dabc3/cells-13-00097-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ab608398718a/cells-13-00097-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ad395f2290f9/cells-13-00097-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/2de31ffc1587/cells-13-00097-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/ab92583880c8/cells-13-00097-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/d25ac6374f51/cells-13-00097-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8042/10778079/def58f6208fa/cells-13-00097-g007.jpg

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Dissecting the immune suppressive human prostate tumor microenvironment via integrated single-cell and spatial transcriptomic analyses.通过整合单细胞和空间转录组分析来剖析免疫抑制性的人类前列腺肿瘤微环境。
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