Nature breakthrough! Targeting TGF-β "cancer environmental immunotherapy" or a new dawn against cancer.

To some extent, the history of human development is a history of constantly fighting disease through intellectual innovation and technological progress.
In the case of cancer, as the understanding progressed, the field of the disease gradually emerged from the situation of no cure, with car-T, PD-1/PD-L1 as the representative of immunotherapy, even once let people see the dawn of cancer.
, the fact that these treatments only work in some patients has prompted researchers to actively search for new cancer immunotherapy.
, on October 21st, the team of immunologists at the Memorial Sloan Caitlin Memorial Cancer Center in the United States published two "back-to-back" articles, "TGF-β suppresses type 2 immunity to cancer" and "Cancer immunotherapy targeted via TGF-β signalling in TH cells."
these two articles, one is a basic study and the other is a translational study that offers new hope for the fight against cancer in humans.
points out that compared to the "frontal enemy" method of activating the immune system to kill cancer cells, this roundabout method of activating immune cells to initiate wound repair in the tissues around cancer cells is also effective in treating cancer, during which the blood vessels that nourish cancer cells are trimmed and the cancer cells become oxygen-deprived and die.
researchers call this approach "cancer environmental immunotherapy" and have designed an antibody-based drug, 4T-Trap, that has successfully curbed cancer progress in mice.
cells are the key transformational growth factors β (TGF-β) that inhibit tumor development, which is an important promoter of immune stability and immune tolerance, which can inhibit tumor progression caused by precancerote cells and promote tumor diffusion.
, researchers at memorial Sloan Kettering Memorial Cancer Center have shown that blocking TGF-β expression on immune cell T cells inhibits tumor development.
problem is that TGF-β is multi-effect on a variety of T-cell lines, and if these path roads are blocked, they can have serious consequences.
, finding TGF-β potential mechanisms for cancer regulation in the body.
, the researchers believe that CD8-T cells, or cytotoxic T lymphocytes (CTL), may be an entry point to inhibit tumor development.
, tumor growth was not inhibited after the TGF-β of CD8-T cells was removed from the breast cancer mouse model.
this, 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.
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 rebuilds the tumor's vascular system, creating a "protective wall" around the tumor, where cancer cells are unable to obtain nutrients from the vascular tissue and eventually die of lack of oxygen.
in this process, assistive T-cell secretion of IL-4 cytokines play an active role.
Blocking cd4-T cell TGF-β signals induces tumor tissue healing, vascular recombination, and oxygen-deprived associated cancer cell death in fact, as early as the mid-1980s, oncologist Harold Dvorak suggested in an article published in NEJM that tumors are essentially "incurable wounds."
this view is further confirmed by the latest research.
tumors promote growth through inflammatory responses and angiogenesics caused by early tissue damage, but when blood vessels completely expand into damaged tissue, the tumor never enters the late stages of wound healing.
-targeted drug 4T-Trap excelled in mouse trials If the first article revealed the potential for blocking TGF-β signals in CD4-T cells to treat cancer, the researchers provided direct evidence for this theory in the second.
with the help of protein engineering, the researchers developed dual-specific antibodies specific to CD4 and TGF-β, and added anti-human CD4 antibodies, ibalizumab, to achieve the targeting of CD4 plus T cells.
the drug is named CD4TGF-beta Trap (4T-Trap).
to explore the therapeutic effects of 4T Trap in vivo, the researchers bred genetically modified mice that expressed human CD4, and the level of expression of CD4 was comparable to that of human CD4 plus T cells.
4T-Trap has a significant inhibitory effect on tumor growth under a treatment plan of 100 μg/dose, two doses per week.
10 doses of the drug, the vascular system in the mice was basically recombined within six 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 vascular system, causing cancer cells to be oxygen-deprived and cancer cell death in general, and 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.
, Professor Li Ming is working with doctors at the Memorial Sloan Caitlin Memorial Cancer Center to bring the study to clinical use.
References: . . . 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'.