What Is LILRB4 and Its Function in Cancer and Immunity?

The human body’s immune system is a complex network of cells and proteins that defend against disease. Within this system, a protein known as Leukocyte Immunoglobulin-like Receptor B4 (LILRB4) controls immune responses. Also referred to as ILT3, this receptor protein is found on the surface of specific immune cells called myeloid cells. Its role in managing the intensity of immune reactions has made it a subject of medical research.

Function of LILRB4 in a Healthy Immune System

The immune system relies on a variety of receptors to regulate its activity, and LILRB4 is a component of this network. It is mainly expressed on myeloid cells like monocytes, macrophages, and dendritic cells, which act as first responders to infection or tissue damage. These cells identify potential threats and present them to T-cells for a targeted attack. LILRB4 functions as an inhibitory receptor, preventing these myeloid cells from becoming overactive.

This inhibitory function is a built-in safety mechanism. When LILRB4 is activated, it sends signals inside the myeloid cell that dampen its response. This process helps maintain immune balance, or homeostasis, ensuring the immune system does not attack the body’s own healthy tissues. This control ensures the immune system remains vigilant against external threats while tolerating the body’s own cells, a process known as immune tolerance.

LILRB4’s Role in Cancer Progression

The regulatory function of LILRB4 can be manipulated by cancerous tumors to aid their survival. Cancers create a localized, self-protective area known as the tumor microenvironment (TME). Within this TME, cancer cells release molecules that activate the LILRB4 receptor on nearby immune cells, hijacking the immune system’s natural “off-switch.”

One of the molecules tumors use for this purpose is Apolipoprotein E (ApoE). When cancer cells secrete ApoE, it binds to LILRB4 on myeloid cells, triggering the inhibitory pathway. This interaction sends a “stand down” signal to the immune cells that should be recognizing and destroying the tumor, creating an immunosuppressive shield.

This process of immune evasion is a challenge in treating cancer. The expression of LILRB4 has been linked to poorer prognoses in several types of cancer, including acute myeloid leukemia (AML). In AML, for instance, LILRB4 activation not only suppresses T-cells but also promotes the infiltration of leukemia cells into other tissues.

Targeting LILRB4 for Cancer Therapy

The discovery of LILRB4’s role in tumor immune evasion has opened a new avenue for immunotherapy. This approach focuses on helping the patient’s own immune system fight cancer. For LILRB4, the primary strategy involves developing drugs that can block the receptor, often monoclonal antibodies engineered to target the LILRB4 protein.

These anti-LILRB4 antibodies work by physically binding to the LILRB4 receptor on myeloid cells. This binding action blocks ligands like ApoE from attaching and sending the inhibitory signal. By obstructing this connection, the therapy “releases the brakes” on the immune cells, allowing them to become properly activated to recognize and attack tumor cells.

Preclinical studies and early clinical trials have shown promising results for this strategy. Another approach involves creating antibody-drug conjugates (ADCs), which link a cancer-killing agent to an anti-LILRB4 antibody. This method allows for the targeted delivery of a toxin to cancer cells expressing LILRB4, minimizing damage to healthy cells.

LILRB4 in Other Diseases

While much of the research focus has been on cancer, LILRB4 plays a part in other diseases characterized by immune dysregulation. Studies have connected the protein to neurodegenerative conditions such as Alzheimer’s disease. In the brain, immune cells called microglia are responsible for clearing protein buildups, including the amyloid plaques associated with Alzheimer’s. Research suggests that APOE found in these plaques can bind to LILRB4 on microglia, hindering their ability to clear the damaging plaques.

Therapeutic strategies targeting this interaction are being explored. In mouse studies, an antibody that blocked the binding of APOE to LILRB4 on microglia successfully mobilized these immune cells to clear amyloid plaques.

LILRB4 has also been implicated in cardiovascular conditions like atherosclerosis, where chronic inflammation in the arteries leads to plaque buildup. In these cases, LILRB4 expression on macrophages may help suppress the inflammatory response that drives the disease.