Scientists at the Weizmann Institute of Science have developed molecules that transform macrophages from tumor protectors into cancer-suppressing cells.
The work was published in the journal Cell.
Immunotherapy has changed the way cancer is treated, but many patients do not respond to therapy or experience relapses. Scientists have long tried to understand how tumors suppress the immune response.
The new research focuses on macrophages, large cells of the immune system that normally perform protective functions, but in tumors often become cancer defenders. Co-author Professor Ido Amit explains: “We know that macrophages can be both a problem and a solution. Tumors hijack them to suppress the immune response. Our goal is to ‘re-educate’ these cells, not remove them.”
The team identified a subset of macrophages with high expression of the TREM2 receptor. It is these macrophages that actively suppress the immune response. Patients with such macrophages in their tumors respond less well to treatment and have lower survival rates.
In the new work, the researchers created molecules called MiTE that simultaneously block TREM2 macrophages and activate killer immune cells. The main problem that scientists have encountered is the side effects of excessive activation of the immune system throughout the body. Scientists equipped MiTE with a molecular “mask” that is removed by special enzymes only in the tumor, where the molecule is activated.
The researchers found that TREM2 macrophages reside next to exhausted killer cells that are unable to cope with the tumor. MiTE blocks immune-suppressing macrophages and simultaneously activates killer cells directly in the tumor.
In experiments on mice, MiTE molecules caused tumors to shrink and the immune system to restructure. In renal cell carcinoma samples from patients, the molecules showed activation of killer cells. Scientists believe that MiTE molecules provide a new method for enhancing cancer immunotherapy.