Nature Magazine First Proposed Cancer Environmental Immunotherapy with Broad Application Prospects

Although immune-based cancer treatments have achieved remarkable success, not everyone responds to these methods, and cancer recurrence can occur. Scientists all over the world are racing to find ways to improve the therapeutic effects of immunotherapy in the human body. However, in two new studies, researchers from research institutions such as the Memorial Sloan Kettering Cancer Center and Cornell University pointed out that this may be too narrowly focused on this issue. Related research results were recently published in the journal of Nature.

According to Dr. Ming Li, an immunologist at Memorial Sloan-Kettering Cancer Center and the corresponding author of the two papers, most existing immunotherapies, including immune checkpoint blockade and CAR-T cell therapy, are designed to promote The immune system finds and kills cancer cells---this is a frontal attack on disease.

However, tumors also need a supportive environment---a safe harbor, where they can thrive. Dr. Li said, "They need blood vessels to provide them with nutrition." Can destroying these safe ports indirectly deal with this internal enemy? Dr. Li believes that the answer is yes, and he supports this concept in these two papers.

He said, “We know that the immune system is very good at identifying harmful invaders and attacking them precisely. But this is not the only way our immune system protects us from threats. It also promotes the healing of damaged tissues, making Pathogens cannot take root in the body. We have now discovered that this latter effect can also be called into the fight against cancer." Dr. Li and his colleagues discovered that they can inhibit cancer in mice by prompting immune cells to start the wound repair process around the tumor. In this process, the blood vessels that feed the cancer are removed, so the cancer cells will starve to death. This is a method called "cancer environment immunotherapy" by Dr. Li.

To understand how wound healing can help curb cancer, consider what happens when a person is injured, such as being cut by a knife. In the early stages, the wound will become inflamed---red, warm, and swollen. At this stage of wound healing, blood vessels expand and immune cells rush in to fight enemies that may cause infection and clean up debris. However, after that, the wound will be filled with new tissue and the inflammation will disappear.

An important role in the wound healing process is a molecule called TGF-β, whose presence changes with the inflammatory cycle. In the presence of cancer "wounds", TGF-β will persist and make cancer growth worse. On the contrary, blocking its effects will inhibit tumor production. Previous studies have shown that this suppression depends on immune cells called T cells.

Dr. Li and his team want to learn more about which T cells are involved in inhibiting cancer growth when TGF-β is blocked. They initially speculated that a subset of T cells called CD8 T cells, or "killer" T cells, is responsible for suppressing tumor production. However, when they genetically removed the TGF-β receptor in mouse CD8 cells, it had no effect on cancer growth.

Next, they wanted to understand whether a different subgroup of T cells, the so-called CD4 T cells, or "helper" T cells, could explain this cancer suppression phenomenon. In fact, genetically removing TGF-β receptors in CD4 T cells can significantly reduce cancer growth in mice.

In this case, how do CD4 T cells promote cancer control? Dr. Li and his colleagues discovered that these cells can promote wound healing around tumors. As part of this process, the blood vessels that provide nutrition to the tumor are significantly remodeled, forming a protective wall around the tumor, depriving the tumor of nutrition. The results of these studies published in the first paper show that blocking TGF-β signaling in CD4 T cells can activate a powerful wound healing response, thereby directly preventing cancer.

But what about tumors that have grown? Can blocking TGF-β inhibit them? In the second paper, Dr. Li and his team discussed this issue in the second set of experiments. They designed an antibody-based drug that can simultaneously bind to TGF-β and helper T cells (Th cells). They found that the drug they called 4T-Trap could significantly reduce cancer in mice.

Previous attempts to block TGF-β to treat cancer were unsuccessful. This may be because this protein has many effects in the body, so blocking it completely may cause serious side effects, such as heart problems, or even new cancers. . However, 4T-Trap targets the TGF-β blocking molecule directly to CD4 T cells, so side effects will be reduced. In other words, this is a more targeted approach.

In fact, the fact that CD4 helper T cells rather than CD8 killer T cells play a key role surprised these researchers. Dr. Li said, "Nowadays, CD8 cytotoxic T cells that recognize cancer cells have become the focus. If it is mediated by T cells, then it must be CD8 T cells. This is almost a dogma. This is our original hypothesis. But the facts proved otherwise."

However, these findings are not entirely without precedent. In fact, the discovery that promoting wound healing can greatly curb cancer progression is well combined with previous research work. In the mid-1980s, cancer researcher Harold Dvorak published a now-famous article titled "Tumors: Wounds That Do Not Heal" in the New England Journal of Medicine. In this article, he believed that the nature of tumors The above is a "non-healing wound". Tumors use normal wound healing to help their growth. They thrive by enlisting an early immune response against tissue damage--for example, the growth of new blood vessels, but when these blood vessels are removed, they can never enter the later stages of wound healing.

Dr. Li said, "By blocking TGF-β in helper T cells, we let wound healing run to completion. We healed cancer wounds." After reviewing his findings and echoing these early findings, Li The doctor said, "This is an exciting return."

He proposed that such "environmental cancer immunotherapy" may become a powerful supplement to current immune-based cancer treatment methods. His laboratory is currently collaborating with doctors and researchers at Memorial Sloan Kettering Cancer Center to translate these new findings into clinical practice.