Programmed Death-Ligand 2 (PD-L2) is a protein found on the surface of various cells. It functions as a regulatory component of the immune system, influencing how immune cells respond to signals and ensuring a balanced immune reaction.
Understanding Immune Checkpoints
The body’s immune system uses a sophisticated network of “checkpoints” to regulate its activity, preventing it from attacking healthy tissues. One prominent example is the Programmed Death-1 (PD-1) receptor, which is found on the surface of activated T cells, a type of immune cell responsible for identifying and eliminating threats.
PD-1 interacts with specific proteins called ligands, which are expressed on other cells. The two known ligands for PD-1 are Programmed Death-Ligand 1 (PD-L1) and Programmed Death-Ligand 2 (PD-L2). When PD-1 binds to either PD-L1 or PD-L2, it delivers an inhibitory signal to the T cell, effectively “turning off” or dampening its immune response.
This interaction is a natural mechanism for maintaining immune tolerance, ensuring the immune system does not mistakenly target the body’s own healthy cells, which could lead to autoimmune diseases. However, certain diseases, particularly cancers, can exploit these checkpoints. Cancer cells can express PD-L1 or PD-L2 on their surfaces, using this pathway to evade detection and destruction by the immune system, allowing tumors to grow unchecked.
PD-L2’s Function in the Body
PD-L2 plays a role in maintaining immune tolerance, the body’s ability to distinguish between self and non-self, preventing autoimmune attacks. Studies involving PD-L2-deficient mice have shown increased T cell activation and abrogated T cell tolerance to oral antigens, indicating its role in negatively regulating T cells and maintaining immune tolerance. PD-L2 is found on various immune cells, including B lymphocytes, dendritic cells, and macrophages. It is also expressed on intestinal stromal cells, where it contributes to immune tolerance. Its expression on dendritic cells can be induced by cytokines such as interleukin-4 (IL-4) and granulocyte-monocyte colony stimulating factor (GM-CSF).
Beyond its normal function, PD-L2 also plays a role in disease, particularly in cancer. Cancer cells, or cells within the tumor microenvironment, can express PD-L2 to help tumors evade immune detection and destruction. This leads to an immunosuppressive environment that hinders the immune system’s ability to fight the cancer. For instance, PD-L2 can be upregulated in senescent cancer cells, creating a unique signature that suppresses immune cell activity, specifically affecting CD8+ T cells.
While both PD-L1 and PD-L2 bind to PD-1 and suppress T cell activity, differences exist in their expression patterns and roles. PD-L2 has a higher binding affinity for PD-1, estimated to be two to six times stronger than PD-L1. PD-L1 is widely expressed in inflamed tissues and on various hematopoietic and non-hematopoietic cells. In contrast, PD-L2 expression is more restricted, primarily found on antigen-presenting cells such as dendritic cells, macrophages, and some B cells. PD-L1 expression can be upregulated by interferon-gamma (IFN-γ), while PD-L2 expression is strongly induced by IL-4.
Harnessing PD-L2 for Therapy
The understanding of the PD-1/PD-L1/PD-L2 pathway has led to the development of immune checkpoint inhibitor therapies, which aim to “unleash” the immune system against diseases like cancer. These therapies work by blocking the inhibitory signals that prevent T cells from attacking cancer cells. By blocking the interaction between PD-1 and its ligands, these inhibitors allow T cells to regain their ability to recognize and destroy tumor cells.
While PD-L1 has been a primary target for many approved immune checkpoint inhibitors, research increasingly focuses on the role of PD-L2. PD-L2 is expressed in various cancer types, sometimes even in the absence of PD-L1, and its expression can be associated with poor patient outcomes. Blocking PD-L2, either alone or in combination with other therapies, is being explored as a way to enhance anti-tumor immune responses, especially in cancers where PD-L2 expression is prominent.
Ongoing research investigates several ways to harness PD-L2 for therapeutic benefit. This includes developing new inhibitors that specifically target PD-L2, or exploring combination therapies that target both PD-L1 and PD-L2. Additionally, PD-L2’s expression patterns are being studied as potential biomarkers to predict how patients might respond to existing PD-1 axis therapies. For example, studies have shown that PD-L2 expression can correlate with anti-tumor immune responses and may predict sensitivity to PD-1 blockade therapy in certain cancers like renal cell carcinoma and lung squamous cell carcinoma.