SIRPα (Signal Regulatory Protein Alpha) is a protein found on the surface of immune cells, particularly macrophages and dendritic cells. It regulates immune responses by acting as a checkpoint, influencing how these cells interact with others. As a transmembrane glycoprotein, SIRPα spans the cell membrane, helping the immune system distinguish between healthy host cells and foreign invaders or diseased cells.
The “Don’t Eat Me” Signal
SIRPα functions by interacting with CD47, a protein widely present on the surface of most healthy cells, including red blood cells and platelets. When SIRPα on an immune cell, such as a macrophage, binds to CD47 on another cell, it triggers an inhibitory signal. This signal tells the macrophage not to engulf or “eat” the cell displaying CD47. This interaction is often called the ‘don’t eat me’ signal.
This interaction acts as a protective mechanism for healthy cells, preventing the immune system from mistakenly attacking the body’s own tissues. The binding of CD47 to SIRPα sends internal signals within the macrophage that prevent it from initiating phagocytosis, the process of engulfing and breaking down other cells.
This “don’t eat me” signal is key to immune self-tolerance. It allows macrophages to survey the body for threats while recognizing and sparing healthy host cells. Without this communication, the immune system might launch indiscriminate attacks, damaging healthy tissues.
SIRPα’s Impact on Health and Illness
The SIRPα-CD47 pathway maintains the body’s immune balance. In healthy states, this interaction helps immune cells distinguish “self” from “non-self,” preventing autoimmune attacks. For example, it protects red blood cells and platelets from premature clearance by macrophages. This system regulates myeloid cell function, ensuring appropriate immune responses.
However, this pathway is frequently exploited in various illnesses, particularly cancer. Many cancer cells overexpress CD47 on their surface, sending a strong “don’t eat me” signal to evade immune destruction. This overexpression allows tumor cells to hide from immune cells like macrophages and dendritic cells, which would otherwise engulf them. Increased CD47 expression on tumor cells is often associated with a worse clinical prognosis.
Beyond cancer, the SIRPα-CD47 interaction influences other aspects of health and disease. It regulates dendritic cells, which are important for initiating adaptive immune responses. Dysregulation of this pathway has been linked to autoimmune diseases, where the immune system mistakenly attacks healthy tissues. For example, the CD47-SIRPα pathway is involved in the development of certain autoimmune conditions.
SIRPα as a Therapeutic Target
Understanding the SIRPα-CD47 pathway has led to new cancer therapies. The rationale for targeting this “don’t eat me” signal is to disable cancer cells’ ability to evade immune surveillance. By blocking the interaction between SIRPα on immune cells and CD47 on cancer cells, phagocytic cells, primarily macrophages, can then engulf and destroy tumor cells.
Several approaches are being explored to achieve this therapeutic goal. One strategy uses antibodies that block CD47 on cancer cells. These anti-CD47 antibodies prevent CD47 from binding to SIRPα, removing the inhibitory signal and promoting macrophage-mediated phagocytosis. Another approach focuses on engineered SIRPα proteins that act as decoys. These engineered proteins can bind to CD47 on cancer cells, blocking the “don’t eat me” signal and enhancing the immune response.
This strategy can enhance the body’s natural defenses against tumors by activating the innate immune system. Beyond direct phagocytosis, blocking the CD47-SIRPα axis can also lead to broader anti-tumor effects, such as promoting the presentation of tumor antigens to T cells, linking innate and adaptive immunity. This dual action suggests that therapies targeting SIRPα or CD47 could be effective alone or in combination with other immunotherapies.