The protein CD47 is on the surface of many cells in the human body, where it functions as a “don’t eat me” signal to the immune system. Its presence communicates to immune cells that the cell is part of the body and should not be attacked. This system helps the immune system distinguish between healthy tissues and foreign or damaged cells that need to be cleared away. Due to its role in both normal processes and disease, CD47 is a subject of interest in cancer research.
The “Don’t Eat Me” Signal Explained
Within the immune system, a type of white blood cell called a macrophage acts as a cellular “clean-up crew.” These cells patrol the bloodstream and tissues to find and remove old, damaged, or foreign cells. This process of engulfing and digesting other cells is known as phagocytosis.
To prevent macrophages from mistakenly attacking healthy cells, the body uses the CD47 protein. Macrophages have a corresponding protein on their surface called signal-regulatory protein alpha (SIRPα). When a macrophage encounters a healthy cell, the CD47 on that cell binds to the macrophage’s SIRPα.
This binding is like a molecular handshake that triggers a signaling cascade within the macrophage, preventing it from initiating phagocytosis. The CD47-SIRPα connection serves as a checkpoint, ensuring that only appropriate targets are eliminated. This protective signal is present on many normal cells, safeguarding them from the immune system.
CD47’s Role in Cancer Evasion
Cancer cells exploit the CD47-SIRPα pathway to proliferate. Many types of cancer produce significantly higher amounts of CD47 on their surface compared to normal cells, a phenomenon known as overexpression. This amplifies the “don’t eat me” signal, making the cancer cells appear healthy to the immune system.
When a macrophage encounters a cancer cell with high levels of CD47, the strong inhibitory signal overrides other signals that would mark the cell for destruction. This allows tumor cells to evade detection and elimination by the innate immune system, a process called immune evasion.
This immune evasion mechanism is observed in a wide range of malignancies, including hematological cancers like leukemia and lymphoma, and solid tumors such as breast and ovarian cancer. The widespread use of this protective mechanism makes CD47 a promising target for new cancer therapies.
Therapeutic Targeting of CD47
The discovery of CD47’s role in immune evasion led to therapies aimed at disrupting this protective signal. The primary approach uses drugs, such as monoclonal antibodies, designed to block either CD47 on cancer cells or its partner, SIRPα, on macrophages. These treatments are a form of immunotherapy, using the patient’s own immune system to fight cancer.
By introducing an antibody that binds to CD47, the “don’t eat me” signal is neutralized. The antibody physically obstructs the site where CD47 would interact with SIRPα, preventing the inhibitory signal from being sent. This action “unmasks” the cancer cells, making them visible to the immune system.
Once the signal is blocked, macrophages recognize the cancer cells as abnormal. Other signals on the cancer cell surface, known as “eat me” signals, can then predominate, prompting macrophages to engulf and destroy the malignant cells. This strategy reawakens the natural phagocytic function of macrophages.
Clinical Challenges and Future Directions
A challenge in targeting CD47 is that the protein is also present on healthy cells, particularly red blood cells. Blocking CD47 systemically can lead to the unintended destruction of these healthy cells by macrophages, an effect known as an “on-target, off-tumor” toxicity. This can result in anemia, a deficiency of red blood cells, which has been a notable side effect in clinical trials.
To address this, researchers are developing next-generation therapies with improved safety profiles. One approach involves creating bispecific antibodies that recognize both CD47 and another protein found only on tumors. Another strategy is to use CD47 as a docking site to deliver a toxin directly to the cancer cell.
Clinical studies are also exploring anti-CD47 agents in combination with other cancer treatments. Combining these therapies could enhance their overall effectiveness while potentially allowing for lower, less toxic doses of each drug. The goal is to refine these strategies to maximize anti-tumor effects while minimizing harm to healthy tissues.