Scientists invent 'cancer environmental immunotherapy' β targeting TGF-Sera

, the history of human development is a history of constantly fighting disease through intellectual innovation and technological progress. Take cancer as an example, with the deepening of understanding, the field of the disease gradually get rid of the situation of no cure, with CAR-T, PD-1/PD-L1 as the representative of the emergence of immunotherapy even once let people see the dawn of cancer. Of course, the fact that these treatments only work in some patients has prompted researchers to actively look for new cancer immunotherapy.On October 21st, local time, the team of immunologists at memorial Sloan Kettering Memorial Cancer Center in the United States published two "back-to-back" articles, "TGF-β suppresses type 2 immunity to cancer" and "Cancer immunotherapy via targeted TF-β signalling in TH cells". In both articles, one is a basic study and the other is a translational study that offers new hope for the fight against cancer in humans.It is pointed out that compared with this "frontal enemy" method of activating the immune system to kill cancer cells, this roundabout method of activating immune cells to initiate wound repair of tissue around cancer cells is also effective in treating cancer, during which the blood vessels that nourish cancer cells will be trimmed and cancer cells will become oxygen-deprived and die. The researchers called this approach "cancer environmental immunotherapy" and designed an antibody-based drug, 4T-Trap, that has successfully stopped cancer progress in mice.CD4-T cells are the key to inhibit tumor developmentconversion growth factor β (TGF-β) is an important promoter of immune stability and immune tolerance, which can inhibit tumor progression caused by precancerote cells and promote tumor diffusion. Previously, researchers at memorial Sloan Kettering Memorial Cancer Center have shown that blocking TGF-β expression on immune cell T cells can inhibit tumors.The problem is that TGF-β has a multi-effect effect on a variety of T-cell lines, and if these paths are blocked, they can have serious consequences. Therefore, it is important to find β TGF-ability target and the potential mechanism of cancer regulation in the body.Initially, the researchers believed that CD8-T cells, or cytotoxic T lymphocytes (CTL), may be the entry point to inhibit tumor development. However, tumor growth was not inhibited after the TGF-β of CD8-T cells was removed from the breast cancer mouse model. Instead, the researchers turned to auxiliary CD4-T cells and found that the genetic removal of TGF-β in CD4-T cells significantly inhibited tumor development in mice.In further experiments, the researchers found that TGF-β's missing CD4-T cells directly fight cancer development by promoting wound healing in tumor tissue.Blocking TGF-β signal transductivity in CD4-T cells reconstructs the tumor's vascular system, and a "protective wall" is formed around the tumor, where cancer cells are unable to obtain nutrients from the vascular tissue and eventually die of hypoxia. In this process, assisted T-cell secretion of IL-4 cytokines plays an active role.Blocking cd4-T cell TGF-β signals induces tumor tissue healing, vascular recombination, and oxygen-deprived cancer cell deathin fact, as early as the mid-1980s, oncologist Harold Dvorak suggested in an article published in NEJM, tumors are essentially "incurable wounds." The latest research further confirms this view. Tumors promote growth through inflammatory reactions and angiogenesics caused by early tissue damage, but when blood vessels expand completely into damaged tissue, the tumor never enters the late stages of wound healing.The targeted drug 4T-Trap excelled in mouse trialsIf the first article revealed the potential to treat cancer by blocking TGF-β signals in CD4-T cells, the researchers provided direct evidence for this theory in the second.Using protein engineering techniques, the researchers developed dual-specific antibodies specific to CD4 and TGF-β, and added human-resistant CD4 antibodies, ibalizumab, to target CD4-T cells. The drug is named CD4TGF-beta Trap (4T-Trap).To explore the therapeutic effects of 4T Trap, the researchers bred genetically modified mice that expressed human CD4, and cd4 had the same level of expression as human CD4-T cells.Under a treatment plan of 100 μg/dose and two doses per week, 4T-Trap had a significant inhibitory effect on tumor growth. After 10 doses, the vascular system in the mice was basically recombined within 6 weeks, catastrophic cancer cell death occurred in the oxygen-deprived area away from the vascular system, and 4T-Trap therapy inhibited blood vessel leakage. More importantly, 4T-Trap is able to specifically enter the tumor's conductive lymph nodes, effectively suppressing TGF-β signals, which are not possible with common TGF-β inhibitors.4T-Trap recombines the tumor's vascular system, causing the cancer cells to be oxygen-deprived and the cancer cells to die.Conclusionoverall, the researchers believe that pharmacological suppression of TGF-β signals in auxiliary T-cells may be a new type of cancer therapy and a powerful complement to existing cancer immunotherapy. Currently, Professor Li Ming is working with doctors at the Memorial Sloan Caitlin Memorial Cancer Center to bring the study to clinical use. (Biological Exploration):1.TGF-β suppresses type 2 immunity to cancer.2.Cancer immunotherapy via targeted TGF-β signalling blockade in TH cells.3.New studies support the concept of 'cancer environment immunotherapy'.