Science Sub-journal: "Twin Killer" - TGF-beta - walking at both ends of cancer's "positive evil"

Recently, I don't know if you have contributed to the box office of Ang Lee's new work "twin killers". Anyway, explorers have contributed.the plot is inexhaustible, but the starting point of the story is absolutely following the biological upsurge - gene editing and cloning.what is more worth mentioning is that with the support of technology, Will Smith played two roles and staged a "I and I" duel.poster image source: network and such a "Gemini killer" also exists in the cell, more accurately, it, like Will Smith, plays two roles for one person! Recently, researchers from Cambridge University and Basel University have discovered its "cancer promoting" behavior: it opens up a new pathway for tumor immune escape by closely linking the impaired respiratory function of T cells with immunosuppression.and it is the famous "double-sided protein": transforming growth factor - β (TGF - β).DOI: 10.1126/ scisignal.aav3334 Messenger of Justice: tumor suppressor function of TGF - β. Tumor immunotherapy is a kind of treatment that can produce anti-tumor effect by activating the immune system of the body.in recent years, tumor immunotherapy with immune checkpoint as therapeutic target has made exciting progress, which opens up a new way for tumor treatment.among them, TGF - β is a multifunctional cytokine, which can block cell cycle and stop cells in G1 phase by regulating the expression level and function of cell cycle related proteins in the early stage of tumor immunity.at the same time, it can also inhibit cell proliferation and protein translation by inducing the expression of 4ebp1 and CDK inhibitors, thus preventing cell cycle progression.in addition, it also inhibited the expression of CDC25A phosphatase, the key enzyme of cyclin activation in CDK cells, and down regulated the expression of proto oncogene c-myc in most of the cells, thus inhibiting the growth of CDK cells.Dr. Sarah dimeloe, an immunologic biologist at the University of Basel, has since known that TGF - β can inhibit tumor by inhibiting cell proliferation, inducing apoptosis, inhibiting the production of inflammatory factors and cell growth, thus avoiding the early formation of tumors.it is also the characteristic of "justice messenger" of anti-cancer. Dr. Sarah dimeloe, an immunobiologist at the University of Basel, and her colleagues have carried out new research on the cell-specific effect of TGF - β.God of evil: tumor promoting function of TGF - β. In the process of research, Dr. dimeloe and his colleagues found that although the anti-tumor effect of TGF - β seems to be extensive, it can not be ignored that TGF - β has the "cancer promoting effect".in addition, what is more surprising is that TGF - β can not only inhibit the anti-tumor activity of T cells, but also inhibit other anti-tumor abilities of the immune system, so that only TGF - β can break the body's anti-tumor defense forces.how does TGF - β degenerate into a demon step by step? Firstly, it is found that tumor cells promote immune escape by forming immunosuppressive microenvironment.among them, tumor cells can secrete a large amount of TGF - β, which not only domesticates and infiltrates immune cells to inhibit its anti-tumor effect, but also starts the sprouting of tumor new blood vessels to provide the available host blood supply for the tumor to support its growth and proliferation.the production of IFN - γ by TGF - β secreted by tumor is related to Smad phosphorylation, but not nuclear translocation. Secondly, Dr. dimeloe and his researchers analyzed the liquid samples secreted by various human metastatic tumors, and tracked how these TGF - β rich microenvironments affect CD4 T cells. the results showed that TGF - β secreted by tumor can not only damage the metabolism and mitochondrial activity of CD4 T cells, but also produce a key anti-tumor molecule, IFN - γ, which is related to the phosphorylation of Smad Protein (which plays a key role in the process of transferring TGF - β signal from cell surface receptor to nucleus), but not to nuclear translocation. Further studies have shown that TGF - β receptor II (TGF - β RII) on T cells will be specifically deleted. TGF - β will directly enter T cells and bind with Smad Protein in mitochondria, resulting in the phosphorylation of Smad2 protein. Smad2 protein is the key molecule in the formation of mitochondrial complex V (ATP synthase), and phosphorylation will lead to the loss of its function 。 that is to say, TGF - β can damage the ATP coupling respiration of T cells, inhibit the production of interferon - γ (IFN - γ), thus controlling the respiratory function of T cells completely, and becoming an important accomplice of tumor immune escape. this is the first time that T cell metabolism has been linked to tumor immune escape. Dr. dimeloe and his colleagues also found that the cancer promoting effect caused by the "evil" face of TGF - β is consistent in all kinds of cancers. therefore, according to this mechanism, we can develop a kind of small molecule drug, which can target the TGF - β protein produced by tumor and affect CD4 + T cells. end reference: [1] tumor derived TGF - β inhibitors mitochondrial inhibition to suppress IFN - γ production by human CD4 + T cells