抑制 CEBPδ 逆转抗转移免疫细胞耗竭

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 CEBP , 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. CEBP -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, CEBP knockdown restored an RNA-binding protein, ZC3H12D, which captured extracellular mRNA to increase tumoricidal activity. Refreshed NK cells using CEBP -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.