Mouse studies show potential new ways to unlock the power of immunotherapy for cancer patients

Reviewed by Emily Henderson, B.Sc.August 11, 2020

Immunotherapy revolutionizes cancer treatment by stimulating the patient’s own immune system to attack cancer cells, sometimes resulting in a very rapid and complete remission. However, because tumors are notorious for evading immune attack, these drugs work in less than a quarter of patients.

A new study in mice by researchers at the University of Washington School of Medicine in St. Louis shows that the effects of standard immunotherapeutic drugs can be enhanced by blocking the protein TREM2, completely eliminating the tumor. The findings, published in Cell magazine on August 11, point to the possibility of new ways to unlock the power of immunotherapy for more cancer patients.

“In essence, we have discovered a new tool for enhancing tumor immunotherapy,” said Dr. Robert Rock Belliveau, Dr. Marco Colonna, lead author of pathology professors. “We see that antibodies against TREM2 alone suppress the growth of certain tumors, and when combined with immunotherapeutic agents, the tumors are completely rejected. Some anti-TREM2 antibodies are already in clinical trials for another disease. The good news is that we have to do some more work in the animal model to validate these results, but if these works well, we already have a large number of antibodies available. , It’s pretty easy to move on to clinical trials.”

T cellsA type of immune cell that has the ability to detect and destroy tumor cells. In order for the tumor to survive, it creates a suppressive immune environment in the surroundings while suppressing T cells. A type of immunotherapy called checkpoint inhibition causes T cells to wake up from a quiescent state, causing them to begin attacking the tumor. However, if the tumor environment is still immunosuppressive, checkpoint inhibition alone may not be sufficient to eliminate the tumor.

Colonna, an immune system expert, has long studied a protein called TREM2 in the context of Alzheimer’s disease. Alzheimer’s disease is associated with poor performance of brain immune cells. Colonna and the first author, postdoctoral researcher Martina Molgora, said that the same type of immune cell, known as a macrophage, is found in tumors and promotes an environment that produces TREM2 and suppresses T cell activity. I realized that

“When we looked at where TREM2 was in the body, we found that it was expressed at high levels inside the tumor, not outside the tumor,” Colonna said. “This is actually an ideal target as TREM2 has very little effect on peripheral tissues.”

Colonna and Morgola-; with colleagues Robert D. Schreiber, Dr. Andrew M., and Jane M. Barsky, a prominent professor. William Vermi, MD, an immunologist at the University of Brescia; set out to determine whether blocking TREM2 could reduce immunosuppression and enhance T cell killing.

As part of this study, researchers injected mice with cancerous cells to induce sarcoma development. The mice were divided into 4 groups. In one group, mice received an antibody that blocks TREM2. In another group, checkpoint inhibitors. In the third group, both. And the fourth group is placebo. Sarcomas grew steadily in mice that received only placebo. Mice treated with TREM2 antibody or checkpoint inhibitor alone slowed tumor growth, plateaued, or disappeared in some cases. However, all mice that received both antibodies completely rejected the tumor. The researchers repeated the experiment with a colorectal cancer cell line with equally impressive results.

With the help of Associate Professor of Pathology and Immunology, Maxim Artyomov, a graduate student Ekaterina Esaulova who works in the PhD lab, researchers analyze immune cells in tumors of mice treated with TREM2 antibody alone. did. They found that suppressive macrophages were almost absent and that T cells were abundant and active. This indicates that blocking TREM2 is an effective means of enhancing anti-tumor T cell activity.

Further experiments have revealed that TREM2-containing macrophages are found in many types of cancer. To assess the relationship between TREM2 expression and clinical outcomes, researchers have developed The Cancer Genome Atlas, a public database of cancer genetics jointly maintained by the National Cancer Institute and the National Human Genome Institute. I used it. They found that higher levels of TREM2 resulted in shorter survival in both colorectal and breast cancer.

Researchers are now extending their TREM2 research to other types of cancer to see if TREM2 inhibition is a promising strategy for a variety of cancers.

“We confirmed that TREM2 is expressed in more than 200 human cancers and various subtypes, but we tested only the colon, sarcoma, and breast models, so we have other models to test,” Morgola said. Said. “And there are also mouse models with a human version of TREM2.”

Colonna added: “The next step is to create an animal model using human antibodies. If that works, I think we’re ready for clinical trials.”