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Author: Sophia
Reading guide:Current immunization** is only effective in patients with solid tumors that infiltrate immune cells or "hot" tumors. Exonucleotide pyrophosphatase Phosphodiesterase 1 (ENPP1) expression is associated with poor cancer prognosis, but the mechanism is unknown.
On December 20, a new study from Stanford University and the Arc Institute, "Enpp1 is an innate immune checkpoint of the anticancer cgamp sting pathway in breast cancer," was published in the journal The Proceedings of The National Academy of Sciences, research shows:Enpp1 is produced by cancer cells and healthy cells inside and outside the tumor, while high patient Enpp1 levels are associated with immune** drug resistance and subsequent metastasis.
Thaw cold tumors
Immune**, such as pembrolizumab (Keytruda), works by blocking immunosuppressive interactions between cancer cells and T cells, a type of immune cell. However, in order for this to be effective, T cells need to penetrate into the tumor. A subset of so-called "hot" tumors, such as melanoma and lung cancer, can be immune*** but many other tumors, such as breast and pancreatic cancer, are "cold" and have no T-cell infiltration.
In order to heat up cold tumors, LI (Sarafan Chem-H Institute scholar) started with CGAMP, a molecule produced by cells when DNA is damaged, and this damage occurs when cells become cancerous. If left intact, CGAMP activates an immune response through the so-called STING pathway, which helps to heat up the tumor.
LI has previously found that CGAMPs are exported outside the cell, but usually, a protein called Enpp1 chews on these molecular "danger" signals before it triggers a reaction. She proposed that ENPP1 helps keep cold tumors cold. In many cancers, high levels of Enpp1 are associated with poor prognosis, but the protein can perform many actions in the body, thereforeLI began to determine if its cgamp chewing ability was the reason behind its clinical significance.
Research Progress
The contribution of ENPP1 to different stages of tumor development, including initiation, progression, and metastasis, is unknown. Importantly,Our work provides evidence that ENPP1 promotes breast carcinomagenesis (Figure 5B).
In the scrna-seq analysis, comparing the primary tumor and metastases, we noted that CGAMP-sting inhibition contributed more to the pro-metastatic phenotype of Enpp1. We believe that this may be due to increased CGAMP production on carcinogenic trajectoriesBecause we showed that Cin high pro-metastatic KI2C+ cancer cells express higher levels of CGAS (Figure 3A).
While a previous study attributed the increasing role of ENPP1 hydrolyzed CGAMP in metastasis to it replacing ATP as the primary eado**, we propose an alternative explanation,i.e., direct inhibition of cgamp-sting activation is the culprit of metastasis. A causal relationship between Enpp1 levels and metastasis in TME is well established, with evidence that disruption of the CGAMP hydrolytic activity of Enpp1 replicates Enpp1 deletion in a completely eliminated metastasis.
Conclusions of the study
In this study, we utilized a mouse model system, and when we removed the cgamp hydrolytic activity of Enpp1, we observed an impressive anti-metastatic effect, which reflects the survival advantage of breast tumor patients with low expression of Enpp1. We determined that Enpp1 expression is an on-off switch for controlling whether breast cancer will metastasize in a sting-dependent manner in a mouse model. In addition, low expression of ENPP1 in pre-biopsy samples obtained from breast cancer patients demonstrated their response to pembrolizumab (anti-PD-1) as neoadjuvant and long metastasis-free survival (DMFS) of up to 7 years.
Enpp1 depletion A model of the mechanism of inhibition.
In conclusion, we conclude thatENPP1 is an innate immune checkpoint that inhibits the activation of the STING pathway in the tumor microenvironment (TME), and targeting the CGAMP hydrolytic activity of ENPP1 can significantly increase the number of patients with a complete response to anti-PD-1.
References: Note: This article aims to introduce the progress of medical research and cannot be used as a reference for ** scheme. If you need health guidance, please visit a regular hospital.
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