CD73, also known as Ecto-5′-nucleotidase or NT5E, is an enzyme anchored to the outer surface of various cells throughout the body. This protein plays a role in the purinergic signaling pathway, a complex system of communication involving molecules derived from nucleic acids. CD73’s enzymatic activity directly controls the production of adenosine, a powerful signaling molecule that influences cellular behavior. Its function is relevant in regulating processes like inflammation and immune response. Misregulation of the enzyme is a key factor in several diseases, most notably in promoting the progression and immune evasion mechanisms of various cancers.
The Core Function of CD73: Converting AMP to Adenosine
CD73 is a glycosylphosphatidylinositol (GPI)-linked protein, tethered to the cell membrane by a lipid anchor, placing its catalytic domain in the extracellular space. Its specific role is to act on adenosine monophosphate (AMP), a nucleotide that is a precursor to adenosine. The enzyme cleaves a single phosphate group from the AMP molecule, a process known as dephosphorylation.
This enzymatic reaction results in the formation of extracellular adenosine and inorganic phosphate. The AMP substrate is generated by another enzyme, CD39 (Ecto-ATPase), which first breaks down extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP). The sequential action of CD39 and CD73 is the primary mechanism for generating extracellular adenosine. This process converts the pro-inflammatory signals of extracellular ATP into the anti-inflammatory and immunosuppressive signal of adenosine.
Regulating Immune Responses and Inflammation
The adenosine generated by CD73 acts as a key component in maintaining immune homeostasis throughout the body. In the context of normal tissue injury, cells often release ATP, which is a potent danger signal that triggers an inflammatory response. The subsequent action of CD73 and CD39 quickly converts this pro-inflammatory ATP into anti-inflammatory adenosine.
This adenosine then binds to specific receptors on immune cells, particularly the A2A and A2B receptors. The binding of adenosine to these receptors dampens the immune response, acting as a brake to resolve acute inflammation and prevent tissue damage. CD73-derived adenosine suppresses the activation and proliferation of T cells and inhibits the release of pro-inflammatory cytokines like interferon-gamma and tumor necrosis factor-alpha.
Regulatory T cells (Tregs) often express high levels of CD73, utilizing the enzyme’s activity to suppress the function of other immune cells. This dampening mechanism is necessary for tissue repair following infection or injury.
CD73’s Role in Tumor Growth and Metastasis
In a pathological setting, cancer cells frequently exploit this natural immune-dampening mechanism by over-expressing CD73. This overexpression is observed in many aggressive tumor types, including lung, breast, prostate, and colon cancers, and is often associated with a poor prognosis. The high concentration of CD73 in the tumor microenvironment leads to an overproduction of immunosuppressive adenosine.
This excess adenosine creates an immune-privileged shield around the tumor, a process known as immune evasion. The adenosine binds to the A2A receptors on cytotoxic T cells and Natural Killer (NK) cells, paralyzing their ability to recognize and destroy cancer cells. The immunosuppressive environment promotes the infiltration of other immune-suppressive cells, such as myeloid-derived suppressor cells, which further aids the tumor’s growth.
Beyond its enzymatic function on the immune system, CD73 also directly contributes to metastasis. The enzyme promotes the migration and invasion of cancer cells into distant tissues. Studies suggest that CD73 activity may enhance tumor angiogenesis, the formation of new blood vessels that feed the tumor. Furthermore, the enzyme’s non-enzymatic functions have been implicated in cell adhesion and invasion, separate from the production of adenosine.
Developing Drugs to Inhibit CD73
Given its significant role in cancer immune evasion, CD73 has become a promising target for new cancer therapies. The rationale behind developing CD73 inhibitors is to block the enzyme’s activity, which prevents the formation of immunosuppressive adenosine. By removing this adenosine shield, the goal is to “re-awaken” the body’s immune system to launch an effective anti-tumor response.
Current therapeutic strategies involve two main approaches: monoclonal antibodies and small molecule inhibitors. Monoclonal antibodies, such as oleclumab, are designed to bind specifically to the CD73 protein, blocking its enzymatic site and preventing its function. Small molecule inhibitors are also being developed to directly interfere with the enzyme’s catalytic activity.
CD73 inhibitors are showing promise when used as part of combination therapies. They are often paired with established checkpoint inhibitors, such as those targeting the PD-1/PD-L1 pathway. Combining an anti-CD73 antibody with a PD-L1 inhibitor has demonstrated improved response rates in clinical trials for non-small-cell lung cancer compared to the PD-L1 inhibitor alone. This combination strategy leverages both therapies to simultaneously remove multiple layers of the tumor’s immunosuppressive defense.