Complete elimination of tumor and inhibition of this protein can greatly enhance the effect of immunotherapy

Introduction: immunotherapy has revolutionized cancer treatment by activating the patient’s own immune system to attack cancer cells. In some cases, it can significantly and rapidly alleviate cancer. But as we all know, tumors are good at avoiding immune attacks, so these drugs are only effective in less than a quarter of patients. Recently, some researchers found that blocking a protein can greatly enhance the effect of immunotherapy, and even can completely eliminate tumor.

T cells, as important immune cells in the human body, have the ability to detect and destroy tumor cells. However, tumor can produce an inhibitory immune environment in and around itself, thus maintaining T cells in an inhibitory state. Recently, researchers from Washington University School of medicine in St. Louis found that blocking TREM2 protein can enhance the effect of standard immunotherapy drugs and even eliminate tumors completely. The study may reveal potential new ways to make immunotherapy effective for more cancer patients.

Dr. Marco Colonna and Dr. Robert rock Belliveau, senior authors of the study, said: “in essence, we have found new tools to enhance tumor immunotherapy. The antibody against TREM2 alone can reduce the growth of some tumors, and when we combine it with immunotherapy, we can see that the tumor is completely rejected. Happily, some anti TREM2 antibodies have entered clinical trials for another disease. We have to do more work in animal models to validate these results, and if it works, we will be able to enter clinical trials quite easily, because there are many antibodies available at the moment. ”

T cells are immune cells with the ability to detect and destroy tumor cells. However, in order to survive, tumor creates an inhibitory immune environment in and around the tumor, which keeps T cells in an inhibitory state. An immunotherapy called checkpoint suppression wakes T cells out of inhibition so they can start attacking tumors. However, if the tumor environment still has immunosuppressive effect, checkpoint inhibition alone may not be enough to eliminate the tumor.

as an expert in the immune system, Professor Colonna has long been studying a protein called TREM2, which is related to the poor performance of immune cells in the brain. Colonna and first author, postdoctoral researcher Dr. Martina molgora realized that the same immune cells, macrophages, were found in tumors, which produced TREM2 and promoted an environment that inhibited T cell activity.

Colonna said: “when we looked at the location of TREM2 in vivo, we found that it was highly expressed inside the tumor rather than outside the tumor. Therefore, it is actually an ideal target because if it is targeted at TREM2, it has little effect on the peripheral tissue. ”

as part of this study, the researchers injected cancer cells into mice to induce the development of sarcoma. The mice were divided into four groups. In one group, mice received antibodies that blocked TREM2. In the other group, one checkpoint inhibitor was given; in the third group, both; and in the fourth group, placebo. In mice receiving only TREM2 antibody or checkpoint inhibitors, tumor growth was slower and tended to stagnate and disappeared in a few cases. But all mice that received both antibodies completely rejected the tumor. The researchers repeated the experiment using colorectal cancer cell lines, and the results were equally surprising.

with the help of Ekaterina esaulova, a graduate student working in the laboratory of Dr. Maxim artyomov, associate professor of pathology and immunology, the researchers analyzed the immune cells in mice tumors treated only with TREM2 antibody. They found that the number of suppressive macrophages is large and the number of T cells is abundant and active, which indicates that blocking TREM2 is an effective way to enhance the activity of anti-tumor T cells.

further experiments showed that macrophages with TREM2 were found in many cancers. To assess the relationship between TREM2 expression and clinical outcomes, we turned to the cancer genome map, a public database of cancer genetics maintained by the National Cancer Institute and the National Human Genome Institute. They found that higher levels of TREM2 were associated with shorter survival in colorectal cancer and breast cancer.

at present, researchers are extending their research on TREM2 to other types of cancer to see if inhibition of TREM2 is a potential strategy for fighting cancer.

molgora said: “we found that TREM2 was expressed in more than 200 cases of human cancer and different subtypes, but we only tested models of colon cancer, sarcoma and breast cancer, so there are other models that need to be tested as well. In addition, we have a mouse model carrying human TREM2. ”

Colonna added: “the next step is to establish animal models using human antibodies. If that works, I think we can start clinical trials. ” 08/16/2020