CLEC12A, formally known as C-type lectin domain family 12 member A, is a protein found in the human body. This protein is encoded by the CLEC12A gene and belongs to a larger group of proteins called the C-type lectin/C-type lectin-like domain (CTL/CTLD) superfamily. Members of this superfamily share a similar structure and are involved in various biological processes, including cell adhesion, cell-to-cell communication, and immune responses. CLEC12A itself is a receptor that plays a role in regulating the immune system.
Understanding CLEC12A
CLEC12A is a protein located on the surface of certain immune cells, particularly myeloid cells such as granulocytes, monocytes, macrophages, and dendritic cells. As a C-type lectin, it binds to specific carbohydrate structures or other molecules. CLEC12A is a transmembrane protein, spanning the cell’s outer membrane, with parts inside and outside. Its extracellular part contains the C-type lectin-like domain (CTLD) for ligand binding. Its intracellular portion contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), important for signaling.
CLEC12A’s Role in the Immune System
CLEC12A functions as an “inhibitory receptor” within the immune system, acting to regulate immune cell activation. This role prevents excessive inflammation and damage to healthy tissues. When ligands bind to CLEC12A’s extracellular domain, it triggers intracellular events. Ligands include components from damaged cells (e.g., monosodium urate crystals, associated with gout), DNA from neutrophil extracellular traps (NETs), and pathogen-associated molecules like hemozoin from Plasmodium parasites or mycolic acid from mycobacteria.
Upon ligand binding, CLEC12A’s intracellular ITIM motif becomes phosphorylated. This phosphorylation allows phosphatases like SHP-1 and SHP-2 to attach to CLEC12A. These phosphatases counteract signals that activate myeloid cells, suppressing the immune response. For instance, CLEC12A inhibits neutrophil activation and limits NET formation, a process where neutrophils release DNA to trap pathogens but can also contribute to inflammation. This mechanism helps maintain immune balance, preventing overreactions that could harm the body.
CLEC12A and Disease Connections
The normal function of CLEC12A in dampening immune responses can be altered or exploited in various diseases. A significant area of research involves its connection to acute myeloid leukemia (AML), a type of blood cancer. In AML, CLEC12A is highly expressed on the surface of leukemic cells, including the cancer stem cells that contribute to disease relapse. This elevated expression on malignant cells, coupled with its low or absent expression on normal hematopoietic stem cells, makes CLEC12A a distinct marker for AML.
The presence of CLEC12A on AML cells suggests it may play a role in how these cancer cells survive and evade the immune system. Researchers have observed a correlation between higher CLEC12A expression and the infiltration of certain immune cells, such as type 2 macrophages and monocytes, which can promote cancer progression. Conversely, lower CLEC12A expression has been linked to a poorer prognosis in AML patients undergoing chemotherapy alone. This indicates that the protein’s expression levels can reflect aspects of the disease’s aggressiveness and response to treatment.
CLEC12A as a Therapeutic Target
Given its high and relatively specific expression on acute myeloid leukemia (AML) cells, CLEC12A has emerged as a promising target for new medical treatments. Scientists are developing various strategies to target CLEC12A for therapeutic benefit, particularly in cancer immunotherapy. One approach involves the creation of bispecific antibodies, such as MCLA-117, which are designed to bind to both CLEC12A on leukemic cells and CD3 on T cells. This binding aims to redirect the patient’s own T cells to specifically recognize and kill the cancer cells, while sparing healthy bone marrow cells.
Another strategy focuses on chimeric antigen receptor (CAR) T-cell therapy, where a patient’s T cells are genetically engineered to express a CAR that specifically recognizes CLEC12A. These CLEC12A-targeted CAR T cells have shown activity against AML cell lines and primary patient samples in preclinical studies, leading to reduced tumor size and improved survival in mouse models. Immunocytokines, which combine an antibody against CLEC12A with an immune-stimulating molecule like IL-15, are also being explored. These agents aim to enhance the activity of natural killer (NK) cells against AML cells while minimizing systemic side effects. The goal of these therapies is to specifically eliminate the cancer cells, including the resilient leukemic stem cells, without harming normal healthy cells.