Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
Department of Biochemistry and Molecular Biology, Shinshu University, School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
Sci Rep. 2023 Mar 8;13(1):3903. doi: 10.1038/s41598-023-30476-4.
The pre-metastatic microenvironment consists of pro-metastatic and anti-metastatic immune cells in the early stages of cancer, when the primary tumor begins to proliferate. Redundantly, pro-inflammatory immune cells predominated during tumor growth. Although it is well known that pre-metastatic innate immune cells and immune cells fighting primary tumor cells become exhausted, the mechanism by which this occurs is unknown. We discovered that anti-metastatic NK cells were mobilized from the liver to the lung during primary tumor progression and that the transcription factor CEBPδ, which was upregulated in a tumor-stimulated liver environment, inhibited NK cell attachment to the fibrinogen-rich bed in pulmonary vessels and sensitization to the environmental mRNA activator. CEBPδ-siRNA treated anti-metastatic NK cells regenerated the binding proteins that support sitting in fibrinogen-rich soil, such as vitronectin and thrombospondin, increasing fibrinogen attachment. Furthermore, CEBPδ knockdown restored an RNA-binding protein, ZC3H12D, which captured extracellular mRNA to increase tumoricidal activity. Refreshed NK cells using CEBPδ-siRNA with anti-metastatic abilities would work at metastatic risk areas in the pre-metastatic phase, resulting in a reduction in lung metastasis. Furthermore, tissue-specific siRNA-based therapy in lymphocyte exhaustion may be beneficial in the treatment of early metastases.
转移前微环境由癌症早期原发性肿瘤开始增殖时的促转移和抗转移免疫细胞组成。在肿瘤生长过程中，促炎免疫细胞占主导地位，这是冗余的。尽管众所周知，转移前固有免疫细胞和抵抗原发性肿瘤细胞的免疫细胞会衰竭，但这种情况发生的机制尚不清楚。我们发现，在原发性肿瘤进展过程中，抗转移 NK 细胞从肝脏动员到肺部，而在肿瘤刺激的肝脏环境中上调的转录因子 CEBPδ 抑制 NK 细胞附着在富含纤维蛋白原的肺血管床上，并对环境 mRNA 激活剂敏感。用 CEBPδ-siRNA 处理的抗转移 NK 细胞再生了支持在富含纤维蛋白原的土壤中附着的结合蛋白，如纤连蛋白和血栓调节蛋白，增加了纤维蛋白原的附着。此外，CEBPδ 敲低恢复了一种 RNA 结合蛋白 ZC3H12D，它捕获细胞外 mRNA 以增加肿瘤杀伤活性。使用具有抗转移能力的 CEBPδ-siRNA 刷新 NK 细胞将在转移前阶段的转移风险区域发挥作用，从而减少肺转移。此外，针对淋巴细胞耗竭的组织特异性 siRNA 疗法可能有益于早期转移的治疗。
