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New checkpoint: A20 downregulation promotes lung cancer immune escape
New checkpoint: A20 downregulation promotes lung cancer immune escape. Science: A20 downregulation promotes lung cancer immune escape, a new checkpoint for lung cancer development?
Tumor cells express immunoregulatory factors to reshape the tumor microenvironment (TME) and promote tumor immune escape, which is a sign of cancer progression. Therefore, TME targeted therapy to break tumor-induced immune tolerance is a research hotspot. Among them, a major advancement is the development of immune checkpoint inhibitors.
Lung cancer has the highest mortality rate of all cancers, and treatment options are extremely limited, especially for patients with cancer-causing mutations in the KRAS gene. Some patients respond well to immune checkpoint inhibitor therapy, while most cancer patients are completely ineffective. Therefore, it is necessary to better understand the factors that change the tumor microenvironment (TME) to avoid the administration of expensive and side-effect immune checkpoint inhibitors to non-responders.
Gene mutations that drive tumor evolution will regulate TME, and this will directly affect the effectiveness of immunotherapy. A20, also known as tumor necrosis factor alpha-inducing protein 3 (TNFAIP3), is an effective anti-inflammatory enzyme and a key factor for inflammatory homeostasis. A20 has a wide range of targeting effects, which can promote k48-linked ubiquitination, activate NF-kB, and inhibit apoptosis and autophagy. Various polymorphisms of the A20/TNFAIP3 gene lead to a decrease in the expression of functional gene products and are related to inflammation and autoimmune diseases, but the role of A20 in cancer is still controversial.
Recently, the research team of Vienna Medical University published a research paper titled: Down-regulation of A20 promotes immune escape of lung adenocarcinomas in Science Translational Medicine, a sub-Journal of Science.
The study found that the lack of A20 in tumor cells significantly enhanced the occurrence of lung cancer, and was related to the decline in CD8+ T cell-mediated immune surveillance. In terms of mechanism, this study clarified that A20 is the main immune checkpoint that regulates the TBK1-STAT1-PD-L1 axis, and it is expected to be used to improve the immune checkpoint treatment of patients with lung adenocarcinoma.
K-Ras is a monomeric G protein that exists in the NF-kB signaling pathway and plays a key role in the growth of malignant tumors. KRAS mutant lung cancer often occurs in chronically inflamed lungs, especially in heavy smokers. The research team analyzed the TCGA data of patients with lung adenocarcinoma. They found that two patients had K-RAS driver mutations and were accompanied by a deletion of the TNFAIP3 gene encoding the A20 protein. A20 is down-regulated in tumor tissues, and there is a direct correlation between the life expectancy of patients and the expression of this protein. In a mouse model of KRAS mutant tumors, the research team found that A20 inhibited the progression of lung adenocarcinoma driven by K-Ras.
Next, the research team aims to understand the molecular mechanism of A20 down-regulation to promote tumor immune escape. They performed RNA sequencing and GSEA marker gene set to analyze the expression of lung adenocarcinoma genes in A20 knockout mice. The results show that the change of IFN signal is essential for the tumor suppressor function of A20.
Data from different cancer patients indicate that IFN signals inherent in tumor cells play an important role in the response to ICB treatment. Therefore, the research team created an A20 loss-of-function model. Interestingly, it can be seen from the overall survival and progression-free survival that melanoma patients with higher A20 LOF markers respond better to PD-1 block. The results of ICB treatment model mice also proved that low A20 expression in tumors leads to an increase in IFN expression gene characteristics, making these tumors more likely to benefit from ICB treatment.
In general, the study revealed the tumor suppressor function of A20 in lung adenocarcinoma, and clarified that A20 is the main immune checkpoint that regulates the TBK1-STAT1-PD-L1 axis. A20 is expected to be used to optimize the immunity of patients with lung adenocarcinoma The checkpoint is under treatment.
(source:internet, reference only)