B7-H3, also known as CD276, is a protein found on the surface of various cells. It has emerged as a significant focus in cancer research due to its distinct expression patterns in diseased tissues compared to healthy ones. This makes it a promising target for new cancer treatments.
Understanding B7-H3’s Function
The immune system maintains a delicate balance through mechanisms known as immune checkpoints. These regulatory molecules either stimulate or inhibit immune responses to ensure proper function and prevent harm to the body’s own tissues. B7-H3 belongs to the B7 family of these checkpoint proteins, interacting with receptors on immune cells, particularly T-cells, to modulate their activity.
The precise natural function of B7-H3 remains an area of active scientific investigation. While initially thought to co-stimulate the immune response, many studies now indicate it primarily plays a co-inhibitory role on T-cells, helping to suppress their activity. Unlike some other well-characterized checkpoints, the specific receptor that B7-H3 binds to is still being fully elucidated.
The Role of B7-H3 in Cancer Progression
When B7-H3 is overexpressed on tumor cells, it actively contributes to cancer progression. One significant role is in immune evasion, helping cancer cells avoid detection and destruction by the body’s immune cells, especially T-cells. It can inhibit T-cell proliferation and reduce anti-tumor cytokine production, creating an environment that protects the tumor.
B7-H3 also actively promotes tumor growth and metastasis. It facilitates the unchecked multiplication of cancer cells and aids in their ability to spread to distant parts of the body. B7-H3 influences cellular processes such as cell proliferation, migration, and invasion. Furthermore, it can promote angiogenesis, the formation of new blood vessels that supply nutrients to the growing tumor.
The elevated presence of B7-H3 on tumor cells often serves as a prognostic marker. High levels of B7-H3 expression are frequently associated with more aggressive forms of cancer and a less favorable outcome for patients. This overexpression can also contribute to therapy resistance, making treatment more challenging.
Cancers Associated with B7-H3 Expression
B7-H3 is broadly expressed across a wide range of human malignancies. It is commonly found at high levels in many solid tumors, indicating its widespread involvement in cancer pathology.
Specific cancers where B7-H3 overexpression has been observed include prostate cancer, non-small cell lung cancer, breast cancer, pancreatic cancer, colorectal cancer, and glioblastoma. High B7-H3 expression has also been detected in ovarian cancer, melanoma, and renal cell carcinoma, with studies showing its presence in a significant percentage of tumor samples.
Therapeutic Strategies Targeting B7-H3
The widespread overexpression of B7-H3 in various cancers, while being minimally expressed in healthy tissues, makes it an attractive therapeutic target. These strategies aim to harness the immune system or deliver targeted treatments directly to cancer cells expressing B7-H3.
One prominent strategy involves Antibody-Drug Conjugates (ADCs), designed to deliver potent chemotherapy directly to cancer cells. An antibody specifically recognizes and binds to B7-H3 on the tumor cell surface, and once bound, the attached toxic drug is released inside the cell, minimizing harm to healthy cells. Examples like MGC018 and DS-7300a are currently being investigated in clinical trials for their B7-H3 targeting capabilities.
Another approach is CAR-T cell therapy, which involves re-engineering a patient’s own immune cells. T-cells are collected from the patient, genetically modified in a laboratory to express a Chimeric Antigen Receptor (CAR) that specifically recognizes B7-H3, and then re-infused into the patient. These modified T-cells are trained to seek out and destroy any cancer cells displaying B7-H3 on their surface.
Monoclonal antibodies are also being developed to directly block B7-H3’s function. These antibodies bind to B7-H3 on tumor cells, preventing it from interacting with immune cells and thereby disrupting its ability to shield the tumor from the immune system. Enoblituzumab is an example of a monoclonal antibody being investigated for its ability to counteract B7-H3’s immune-suppressive effects, potentially reactivating T-cells to attack cancer.