CD276, also known as B7-H3, is a protein found on the surface of various cells throughout the human body. It functions as a transmembrane glycoprotein, meaning it spans the cell’s outer membrane, with parts extending both inside and outside the cell. This protein belongs to the B7 family of immune regulatory molecules, involved in fine-tuning immune responses. Its structure includes extracellular immunoglobulin-like domains, a transmembrane segment, and a short tail within the cell.
The Function of CD276 in the Immune System
CD276 plays a complex role in regulating the immune system, particularly in modulating the activity of T-cells, which are a type of white blood cell central to immune responses. It acts as an immune checkpoint molecule, a regulatory switch that can activate or suppress immune cell functions. Immune checkpoints are crucial for maintaining a balanced immune response, preventing the immune system from overreacting and harming healthy tissues.
Research indicates that CD276 exhibits a dual role, capable of both stimulating (co-stimulatory) and suppressing (co-inhibitory) T-cell responses, depending on the specific cellular environment. Initially, it was identified as a co-stimulatory molecule, promoting the proliferation of both CD4+ and CD8+ T-cells and enhancing their cytotoxic activity. However, subsequent studies have also shown its ability to inhibit T-cell activation and proliferation, influencing pathways that regulate immune cell function. CD276 participates in immune regulation, affecting T-cell activation, cytokine production, and immune cell differentiation.
CD276 Expression in Cancer
In contrast to its varied expression in healthy tissues, CD276 is often found in significantly higher amounts on the surface of cancer cells, a phenomenon called “overexpression.” This elevated presence makes it a notable feature in many malignancies compared to most normal cells, where its expression is limited. The increased quantity of CD276 on tumor cells is thought to contribute to tumor development and is often associated with less favorable patient outcomes.
High CD276 expression has been observed across a wide spectrum of human cancers. This includes common types such as prostate, pancreatic, lung, breast, colorectal, ovarian, and renal cancers. For instance, CD276 is significantly elevated in metastatic prostate cancers and is frequently expressed in non-small cell lung cancer tumors. Its widespread presence across diverse tumor types highlights its relevance in cancer biology.
Mechanisms of Tumor Progression
The overexpression of CD276 on cancer cells actively contributes to tumor growth and spread through several distinct mechanisms. One significant way it assists tumors is by facilitating immune evasion, allowing cancer cells to escape detection and destruction by the body’s immune system. CD276 on tumor cells can suppress the activity of T-cells, particularly CD8+ cytotoxic T-cells, which eliminate cancerous cells. This suppression can lead to a less effective anti-tumor immune response within the tumor microenvironment.
CD276 also promotes the spread of cancer cells, a process known as metastasis. It helps cancer cells detach from the primary tumor, travel through the bloodstream or lymphatic system, and establish new tumors in distant organs. This pro-metastatic function has been observed in various cancer types.
CD276 can stimulate angiogenesis, the formation of new blood vessels that supply the tumor with nutrients and oxygen. Tumors require a robust blood supply to grow beyond a minimal size, and CD276 helps facilitate this process. It can promote the growth of tumor-associated blood vessels. This ability to support new blood vessel formation aids in tumor progression.
Therapeutic Targeting of CD276
Given its widespread overexpression on many cancer cells and limited presence on most normal healthy tissues, CD276 has become an appealing target for developing new cancer therapies. This differential expression allows for strategies that can selectively target tumor cells while minimizing harm to healthy cells. Various approaches are being developed to leverage CD276’s unique expression pattern in cancer treatment.
One promising strategy involves Antibody-Drug Conjugates (ADCs). A specific antibody that recognizes CD276 on the cancer cell surface is chemically linked to a potent chemotherapy drug. Once the antibody binds to the cancer cell, the complex is internalized, and the chemotherapy drug is released inside, directly delivering its toxic payload to the tumor cells. This targeted delivery aims to increase chemotherapy effectiveness while reducing systemic side effects.
Another approach is CAR-T cell therapy, which involves re-engineering a patient’s own immune cells. T-cells are collected from the patient and modified in a laboratory to express a Chimeric Antigen Receptor (CAR) that specifically recognizes CD276. These re-engineered T-cells are then multiplied and infused back into the patient, where they can identify and destroy cancer cells expressing CD276. This harnesses the patient’s own immune system to mount a precise attack against the tumor.
Monoclonal antibodies (mAbs) are also being developed to target CD276. These lab-made antibodies can bind to CD276 on the surface of cancer cells, either blocking its pro-tumor functions or flagging the cancer cells for destruction by other immune cells. Some monoclonal antibodies can enhance immune cell-mediated cytotoxicity, where immune cells like natural killer (NK) cells are recruited to kill the antibody-coated tumor cells. These diverse therapeutic strategies aim to exploit CD276’s role in cancer to develop more effective and targeted treatments.