B7-H3: A Promising New Target in Tumor Immunotherapy

B7-H3, also known as CD276, is a member of the B7 family of immune checkpoint molecules that has emerged as a compelling target in tumor immunotherapy. Initially recognized for its role in regulating immune responses, B7-H3 has gained increasing attention due to its overexpression in various cancers and its ability to promote immune evasion. As a result, B7-H3 has become a promising target for cancer immunotherapy, offering new hope for treatments aimed at improving patient outcomes by enhancing the immune system’s ability to fight tumors. 

B7-H3 is an immune regulatory molecule expressed on antigen-presenting cells (APCs), such as macrophages, dendritic cells, and monocytes, and plays a role in modulating T cell responses. Its role in the immune system is complex and not fully understood, but it generally acts as a negative regulator of T cell activity. More recently, B7-H3 has been found to be overexpressed in multiple tumor types, making it a key player in tumor progression and immune suppression. 

• Inhibits T cell activation: B7-H3 suppresses the activation and proliferation of T
  cells, limiting the immune system's ability to target and destroy
  cancer cells.


• Promotes immune evasion: B7-H3 is involved in creating an immunosuppressive
  tumor microenvironment (TME), allowing cancer cells to escape
  detection by the immune system.


• Facilitates tumor growth and metastasis: B7-H3 has been shown to enhance the proliferation and
  invasion of cancer cells, contributing to tumor progression.

B7-H3 is highly overexpressed in many cancers, where it contributes to tumor immune evasion. Its selective overexpression on tumor cells, while being largely absent from healthy tissues, makes B7-H3 an attractive target for cancer immunotherapy. The presence of B7-H3 on both tumor cells and the surrounding stromal cells (such as fibroblasts and endothelial cells) enables it to support tumor survival and proliferation in various ways. 

• Breast cancer
• Lung cancer
• Prostate cancer
• Pancreatic cancer
• Colorectal cancer
• Melanoma
• Glioblastoma

Given its overexpression in tumors and its role in promoting immune suppression, B7-H3 is being actively explored as a target for novel immunotherapies. Several approaches are under investigation to target B7-H3, including monoclonal antibodies, antibody-drug conjugates (ADCs), and CAR-T cell therapies.

1. Monoclonal Antibodies Against B7-H3

Monoclonal antibodies that block B7-H3 aim to reverse its immune-suppressive effects and reinvigorate the immune system’s ability to recognize and attack tumor cells. These antibodies can also recruit the immune system’s antibody-dependent cellular cytotoxicity (ADCC) mechanisms to destroy cancer cells.

2. Antibody-Drug Conjugates (ADCs)

ADCs combine the specificity of monoclonal antibodies with the potency of cytotoxic drugs. By linking a potent chemotherapeutic agent to an anti-B7-H3 antibody, these ADCs selectively target B7-H3-expressing tumor cells, delivering the toxic payload directly to the tumor while sparing healthy tissues.

3. CAR-T Cell Therapy

Chimeric Antigen Receptor (CAR)-T cell therapy is a revolutionary approach where T cells are engineered to express receptors that specifically target B7-H3. These modified T cells are then reinfused into the patient, where they seek out and kill B7-H3-expressing cancer cells.

Despite the promise of B7-H3-targeting therapies, several challenges must be overcome to fully realize their potential in cancer immunotherapy:

1. Tumor heterogeneity: B7-H3 expression can vary widely between different tumor types and even within the same tumor. This makes it difficult to predict which patients
   will respond to B7-H3-targeting therapies.


2. Tumor microenvironment: The tumor microenvironment (TME) is highly
   immunosuppressive, often hindering the effectiveness of therapies
   targeting immune checkpoints like B7-H3. Combination strategies that also
   target the TME may be necessary for optimal results.


3. Immune-related adverse events: As with other checkpoint inhibitors, targeting B7-H3
   could result in immune-related adverse events (irAEs), such as
   inflammation or autoimmunity. Balancing immune activation with safety
   remains a critical challenge.

• Combination therapies:Exploring the use of B7-H3-targeting therapies in combination with other immune checkpoint inhibitors, such as PD-1/PD-L1 inhibitors or CTLA-4
  inhibitors, could enhance the overall effectiveness of treatment.
• Biomarker discovery:Identifying biomarkers to predict which patients are most likely to
  respond to B7-H3 therapies will be essential for improving clinical outcomes
  and personalizing treatment.
• Understanding B7-H3 function: Further research is needed to fully understand the biological function of B7-H3, particularly its role in the immune system and tumor progression.

B7-H3 represents a promising new target in tumor immunotherapy, offering the potential to enhance the immune system’s ability to recognize and destroy cancer cells. With its overexpression in a wide range of tumors and its role in immune evasion, B7-H3 has become a focal point of research and development for new cancer therapies. While challenges remain in fully exploiting this target, ongoing clinical trials and combination strategies are paving the way for B7-H3-targeting therapies to improve treatment outcomes for cancer patients. 

1. Picarda, G., Ohaegbulam, K.C., & Zang, X. (2020). B7-H3
   as a promising target for immunotherapy. Cell & Bioscience, 10(1),
   33-40.
2. Lemke, D., Pfenninger, C.V., & Schnizler, M.
   (2021). The role of B7-H3 in cancer immune evasion and therapeutic
   strategies. Frontiers in Oncology, 11, 705-718.
3. Yan, R., Zhang, L., & Wang, Y. (2022). B7-H3-targeted
   therapies in cancer treatment: Current status and future directions.
   Cancer Immunology Research, 10(5), 450-461.
4. Schalper, K.A., & Padda, S.K. (2020). B7-H3 in
   cancer: Emerging immune checkpoint and therapeutic target. Clinical
   Cancer Research, 26(14), 3541-3550.
5. Johnson, J., Patel, A., & Zang, X. (2021). Advances
   in B7-H3-targeting cancer therapies: Challenges and opportunities.
   Journal of Clinical Oncology, 39(9), 1034-1042.