Double-arm Molecules Targeting CLTA-4 and CD47 may Specifically eliminate Treg Cells in Tumors and Effectively Promote Anti-tumor Immune Responses

In a new study, researchers from the University of Texas Southwestern Medical Center, Aetio Biotherapy and the Institute of Biophysics of the Chinese Academy of Sciences found that a double-arm molecule can effectively eliminate cancer-protecting cells (immune Suppress cells) so that the immune system can fight tumors without becoming overactive. This discovery may lead to a new type of cancer immunotherapy.

Researchers say that the immune system can attack cancer without causing harmful autoimmune symptoms by effectively removing these immunosuppressive cells in the tumor rather than the whole body. For decades, scientists have known that the immune system not only plays a key role in fighting cancer through the direct action of killer T cells and other components but also counteracts these effects through immunosuppressive cells called regulatory T cells (Treg). These Treg cells help regulate the immune response by preventing a variety of immune cells from becoming overactive and causing autoimmune diseases. However, they also accumulate in tumors, protecting tumor cells from immune attack.

Treg cells maintain a balance of two proteins---CTLA-4 and CD47--- on their surface. These two proteins send out "eat me" and "don't eat me" signals to phagocytes, so that Treg cells are under control. Various immunotherapies try to increase the "eat me" signal or reduce the "don't eat me" signal to reduce the Treg cells in the tumor. However, each strategy has disadvantages. Increasing the "eat me" signal has the systemic effect of promoting autoimmunity, while reducing the "don't eat me" signal only shows promise in the treatment of blood cancer (such as leukemia).

In order to find a new way to eliminate Treg cells, the researchers constructed a double-arm molecule. This double-arm molecule is a heterodimer that combines anti-CTLA-4 antibody and CD47 ligand SIRPα together, in which the anti-CTLA-4 antibody targets Treg cells, and SIRPα selectively blocks Treg in the tumor CD47 on the cell. They found that this double-arm molecule can simultaneously increase the "eat me" signal and block the "don't eat me" signal, thereby prompting phagocytes to engulf these immunosuppressive cells. When it was injected into a mouse model of colon cancer, they found that it preferentially eliminates Treg cells in tumors, and does not affect Treg cells in other parts of the body, making these mice immune to autoimmune diseases caused by treatment.

However, injecting the same amount of "eat me" enhancer and "don't eat me" blocker into these mice can cause systemic autoimmune side effects which indicates that combining these two effects in one molecule is the key to eliminating Treg cells from tumors. As the number of Treg cells decreased after treatment, the tumors in these mice also shrank significantly. This strategy also worked in mice carrying human lung cancer tumors, which suggests that it may be feasible in human patients.

Reference:

1. Anli Zhang et al. Dual targeting of CTLA-4 and CD47 on Treg cells promotes immunity against solid tumors. Science Translational Medicine, 2021, doi:10.1126/scitranslmed.abg8693.