What Is CD73? Its Role in Cancer and the Immune System
Learn about the CD73 enzyme, whose normal role in regulating immune signals can be exploited by cancer cells to promote tumor survival and growth.
CD73, also known as ecto-5′-nucleotidase, is a protein found on the surface of many cells throughout the body, including those lining our blood vessels and the specialized cells of our immune system. This protein is involved in a wide range of physiological processes. Its newly understood roles in health and disease have made it a subject of significant scientific interest, particularly regarding its function in various medical conditions.
Understanding CD73’s Function
CD73 operates as an enzyme, a type of protein that speeds up chemical reactions. Its specific job is to catalyze the conversion of a precursor molecule, adenosine monophosphate (AMP), into adenosine. This reaction is the final and rate-limiting step for adenosine production, controlling the overall amount that can be made in the extracellular space.
Once produced, adenosine acts as a signaling molecule. It interacts with specific receptors on nearby cells to transmit messages that alter their behavior. The effects of adenosine are widespread, influencing everything from blood flow to nerve function.
CD73 is expressed on many cell types, including endothelial cells that line blood vessels and the stromal and epithelial cells that form tissue frameworks. This allows it to generate adenosine in diverse environments. This widespread distribution helps regulate local cellular activities and maintain tissue stability.
CD73 and the Immune System
The adenosine generated by CD73 dampens immune responses, a protective mechanism that prevents excessive inflammation and potential tissue damage. This function helps maintain balance, or homeostasis, within tissues. When the immune system is activated, CD73 activity increases to produce adenosine, which acts as a brake to keep the response in check.
This immunosuppressive effect is achieved by influencing a wide array of immune cells. Adenosine inhibits the activation and function of T cells, including impairing the activity of CD8+ T cells, which are the immune system’s primary cancer-killing cells. The molecule also suppresses the ability of natural killer (NK) cells to destroy their targets.
Adenosine signaling also shapes the behavior of myeloid cells like macrophages and dendritic cells. It can promote the differentiation of macrophages into an M2 type, which are involved in tissue repair but also have immunosuppressive properties. By modulating these various immune cells, the CD73-adenosine pathway finely tunes the intensity and duration of immune activity.
The Link Between CD73 and Cancer
Many types of cancer cells express high levels of CD73 on their surface, actively exploiting the protein’s function. By overexpressing CD73, cancer cells produce large amounts of adenosine within the tumor microenvironment. This high concentration of adenosine creates a shield of immunosuppression, protecting the tumor from the immune system.
This adenosine-rich environment suppresses the function of tumor-infiltrating T cells and NK cells that would otherwise destroy the malignant cells. This allows the tumor to survive and grow, hidden from a locally disarmed immune system. Consequently, high CD73 expression in tumors is often correlated with a poorer prognosis for patients with cancers like melanoma, breast cancer, and lung cancer.
Beyond evading immune destruction, the adenosine produced by CD73 can directly promote cancer progression. Adenosine signaling can stimulate angiogenesis, the formation of new blood vessels that supply tumors with nutrients. It can also enhance tumor cell proliferation, survival, and metastasis, which is the spread of cancer to other parts of the body.
Developing Therapies Around CD73
CD73’s role in cancer has made it a target for new therapeutic strategies in cancer immunotherapy. The goal of these therapies is to block the immunosuppressive effects of the CD73-adenosine pathway. This “reawakens” the immune system to recognize and attack cancer cells, with many drugs currently being evaluated in clinical trials.
One strategy involves using CD73 inhibitors, such as monoclonal antibodies or small molecule drugs, which bind to CD73 and block its enzymatic activity. By preventing the conversion of AMP to adenosine, these inhibitors reduce the concentration of immunosuppressive adenosine in the tumor microenvironment. This allows anti-tumor immune cells to function more effectively.
Scientists are also exploring combination therapies. Combining CD73 inhibitors with other immunotherapies, such as checkpoint inhibitors that target proteins like PD-1, has shown promise. The rationale is that blocking multiple immunosuppressive pathways at once can produce a more robust and durable anti-tumor immune response.