Nature: Two in the same period! From basic research to drug development, Li Ming's team invented "Cancer Environmental Immunotherapy"

The emergence of cancer immunotherapy, represented by Immune Checkpoint Blockade (ICB), has revolutionized the field of cancer treatment.
some cancer patients who did not respond to traditional chemotherapy, radiotherapy, and targeted therapy had an ideal prognostication after receiving PD-1/PD-L1 antibodies or CTLA-4 antibodies.
However, a large number of clinical trials have shown that most types of cancer patients do not respond well to immunosuperviral therapy, except for some non-small cell lung cancer and melanoma categories of cancer patients who benefit from immuno-checkpoint therapy.
, the life sciences and medicine are actively exploring new cancer immunotherapy.
October 21, 2020, professor Ming Li of the Memorial Sloan Kettering Cancer Research Center published two "back-to-back" articles in nature magazine - TGF-β suppresses type 2 immunity to cancer and Caner immunotherapy via targeted TGF-β signaling in THCells, one of which was a fundamental study and the other a translational study.
most immunotherapy, including immuno-checkpoint blocking and CAR-T therapy, are designed to activate the immune system to directly kill cancer cells as a means of fighting cancer, according to Professor Li Ming.
, the growth and reproduction of tumors also requires a supporting environment, or "safe haven".
, for example, require vascular tissue to provide nutrients.
can I indirectly kill cancer cells by targeting these "safe havens" with immunity? Two Nature papers by Professor Li Ming's team tell us that this idea is feasible.
know that the immune system can accurately identify and remove harmful pathogens, but this is not the only way the immune system protects the body from pathogens.
immune system can also prevent pathogens from "rooting" in the body by promoting the healing of injured tissue.
function of the immune system that promotes tissue healing can also be applied to anti-tumors.
Li Ming's team found that by activating immune cells to initiate tissue repair around cancer cells, it inhibits tumor growth.
process, the vascular tissue that "nourishes" cancer cells is "trimmed" like branches, causing cancer cells to die of hunger.
Li Ming called the treatment "Cancer Environment Immunotherapy".
blocks the TGF-β signaling path on auxiliary T-cells, triggering a wound healing response that reshapes tumor angiogenesy leading to cancer cells dying of hunger in order to understand how the wound healing process inhibits cancer growth, and we can imagine a person being knifed and his wound healing.
, an inflammatory reaction occurs where the injury occurs - redness, heat, and swelling.
at this stage of wound healing, vascular tissue expands near the wound and immune cells gather in the wound to kill the microorganisms that cause infection and remove cell fragments.
but after that, the wound is gradually filled with fresh tissue and the inflammatory response subsides.
TGF-β an important cell molecule in wound healing, which rises and retreats with the inflammatory cycle.
TGF-β in environments where tissue damage is caused by the growth of cancer cells.
previous studies by Professor Li Ming's team have found that blocking TGF-β expression on immune cell T cells inhibits tumor development.
Li Ming's team wanted to continue to explore specific cells that mediate the growth inhibition of cancer cells when TGF-β signals are blocked.
they initially suspected it was CD8 plus T cells, also known as "killer" cells, that mediated the effect.
, however, when they genetically knocked out the expression of TGF-β receptors on CD8-T cells in mice, they found no effect on cancer growth.
next, they wondered if another type of T-cell CD4 plus T-cell, also known as "assistive" T-cells, could explain the cancer's growth inhibition.
sure enough, tumor growth in mice was severely inhibited when the expression of the TGF-β receptor was knocked off on the CD4 plus T cells in the mice.
, how do CD4-plus T cells control cancer growth β TGF-T signaling path is blocked? Professor Li Ming and his team found that these cells are anti-tumor by promoting wound healing in tumor tissue.
in the process, the growth patterns of vascular tissue that provide nutrients to tumor tissue are remodeled and a dense "protective wall" is formed around the blood vessels to prevent cancer cells from ingesting nutrients.
the results, published in the first Nature paper, the authors showed that blocking the TGF-β signaling path on CD4 plus T cells activates a powerful wound healing response that prevents cancer cells from growing.
, if tumor growth has already formed, can it still block tumor growth by blocking the TGF-β signaling path? In the second Nature paper, Professor Li Ming's team answered this question.
4T-Trap reshapes the formation of blood vessels in tumors to inhibit tumor growth They designed an antibody drug that binds both TGF-β and auxiliary T cells.
they named the dual-specific antibody drug 4T-Trap and found it significantly inhibited tumor growth in mice.
Many TGF-β inhibitors have been tried to have anti-tumor effects, but have not been clinically successful, possibly because TGF-β is so powerful and so widespread that it can have significant side effects by completely suppressing it through drugs.
and 4T-Trap can directly and specifically target the TGF-β signaling path on CD4-plus T cells, so the side effects are greatly reduced.
, 4T-Trap is able to specifically enter the tumor's conductive lymph nodes, where the CD4 T-cell TGF-β signaling path is activated during antagonist antigen delivery, which is not possible with ordinary TGF-β inhibitors.
many scholars would find it strange to say that CD4-assisted T cells are more critical to anti-tumor effects than CD8 killer T-cells.
Because CD8 killer T cells are the focus of current research, and we all have an inherent thinking that T-cell-mediated anti-tumor effects, are CD8 killer T-cells mediated, rather than CD4 auxiliary T-cells.
this CD4-assisted T-cell-mediated anti-tumor effect breaks this innate thinking and re-recognizes the role of CD4-assisted T-cells in tumor immunity.
Li Ming points out that the relationship between tumor and wound healing in their study is not entirely original.
fact, in the mid-1980s, oncologist Harold Dvorak published a paper in the New England Journal of Medicine and noted that tumors were essentially "irriageable wounds," which was in line with their findings.
tumor promotes growth through inflammatory reactions and angiogenesics caused by early tissue damage, and when the blood vessels completely expand into the damaged tissue, the tumor never enters the later stages of wound healing.
by blocking the TGF-β signaling path on the auxiliary T cells, we can allow the tumor to complete the wound healing process in its entirety.
review of previous studies, and their findings respond to previous guesses, which is also an exciting regressive study.
the classification of cancer therapies, Professor Li Ming points out that this kind of environmental immunotherapy for cancer is likely to be a new type of cancer therapy, an important complement to existing cancer therapies.
is now working with doctors at memorial Sloan Kettering Cancer Center to bring the treatment to clinical use.
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