The immune system uses immune checkpoints, a complex network of checks and balances, to prevent T-cells from attacking healthy tissues. These checkpoints function like “brakes” that modulate the strength and duration of an immune response. B7-H4 is a recently identified member of the B7 family of co-inhibitory molecules that serves as one such brake. Its expression is frequently dysregulated in human diseases, particularly in oncology. B7-H4 is now intensely investigated for its role in regulating immune responses and its potential as a target for next-generation cancer therapies.
Molecular Identity and Expression
B7-H4 is a protein encoded by the VTCN1 gene (V-set domain containing T cell activation inhibitor 1). It is also known as B7x and B7S1, and structurally belongs to the immunoglobulin superfamily of proteins. As a transmembrane protein, it is anchored in the cell membrane where it interacts with other cells.
In healthy individuals, B7-H4 expression is tightly controlled and typically low or absent in most normal tissues. It can be inducibly expressed on certain immune cells, such as macrophages, dendritic cells, and B cells, usually in response to inflammatory signals. The protein’s limited cell surface display, despite widespread messenger RNA (mRNA) presence, suggests precise regulatory mechanisms.
Historically, understanding B7-H4’s mechanism was hindered because its specific T-cell receptor was unidentified. Research now suggests B7-H4 may signal through a complex involving the semaphorin family member Neuropilin-1, which is upregulated on activated T-cells. The binding of B7-H4 to its receptor delivers the inhibitory message that governs T-cell behavior.
Function in Immune Regulation
The core biological function of B7-H4 is to act as a negative regulator of adaptive immunity by suppressing T-lymphocyte activity. It is classified as a co-inhibitory immune checkpoint, working alongside the primary T-cell activation signal to turn the response down or off. This inhibitory signal is delivered when B7-H4 on an antigen-presenting cell or other cell type ligates its receptor on the surface of a T-cell.
This ligation dampens the T-cell response across several parameters. B7-H4 effectively halts the T-cell’s ability to divide, arresting the cell cycle and preventing clonal expansion. It also limits the production of immune messenger molecules, known as cytokines, such as Interleukin-2 (IL-2) and Interferon-gamma (IFN-\(\gamma\)).
By inhibiting these functions, B7-H4 promotes T-cell anergy or exhaustion, rendering the immune cells functionally inactive. In a healthy context, this role is important for maintaining peripheral tolerance, preventing the immune system from launching destructive attacks against the body’s own cells. Its function is a protective mechanism against inflammatory disease, evidenced by studies showing that mice lacking B7-H4 can develop more severe autoimmune conditions.
B7-H4’s Role in Cancer Progression
Cancer cells hijack natural immune checkpoints, and B7-H4 is one molecule tumors frequently exploit to evade destruction. Overexpression of B7-H4 is observed in a wide variety of solid tumors. This high expression is a factor in creating an immunosuppressive tumor microenvironment.
Tumors use B7-H4 as a molecular shield to protect themselves from immune surveillance. When B7-H4 is expressed on tumor cells or tumor-associated macrophages, it engages with T-cells infiltrating the tumor site. This interaction delivers the “do not attack” signal, neutralizing T-cells attempting to destroy the malignancy.
High B7-H4 expression is consistently linked to poor patient outcomes across many cancer types. This overexpression correlates negatively with the density of tumor-infiltrating lymphocytes (TILs), particularly cytotoxic CD8+ T-cells. The mechanism is clear: fewer active T-cells lead to unchecked tumor growth and progression.
B7-H4 overexpression is associated with more advanced disease stages, increased likelihood of metastasis, and shorter overall and disease-free survival rates. Due to this strong association with disease severity and immune evasion, B7-H4 has emerged as a significant biomarker for predicting prognosis and an appealing therapeutic target. Targeting this molecule offers a strategy to re-engage the immune system and overcome tumor resistance.
Cancers with B7-H4 Overexpression
B7-H4 overexpression is observed in cancers of the:
- Ovary
- Breast
- Lung
- Kidney
- Endometrium
Developing Targeted Therapies
The function of B7-H4 in suppressing anti-tumor immunity makes it a promising target for therapeutic development in precision medicine. The primary strategy involves blocking the B7-H4 signal to release the immune system’s brakes, allowing T-cells to mount an effective attack. While early research focused on monoclonal antibodies to block the B7-H4/receptor interaction, the current focus has shifted to more direct approaches.
The most advanced therapeutic avenue involves the development of Antibody-Drug Conjugates (ADCs). An ADC combines a specific anti-B7-H4 antibody with a potent chemotherapy agent. The antibody acts as a homing device, recognizing and binding to the B7-H4 protein highly expressed on the surface of cancer cells.
Once bound, the complex is internalized by the cancer cell, and the toxic payload is released inside, leading to targeted cell death. This mechanism allows for the precise delivery of chemotherapy directly to B7-H4-expressing tumors while minimizing systemic toxicity. Several B7-H4 targeted ADCs, such as felmetatug vedotin (SGN-B7H4V), puxitatug samrotecan (AZD8205), and XMT-1660, are currently being investigated in Phase 1 and Phase 2 clinical trials for various solid tumors, including triple-negative breast cancer and ovarian cancer.
B7-H4 targeted therapies represent the next generation of immune oncology drugs, expanding beyond established targets like PD-1 and PD-L1. Researchers are also exploring the potential for B7-H4 ADCs to be used in combination with existing immune checkpoint inhibitors. This combination approach aims to simultaneously destroy tumor cells with the toxic payload while reactivating the T-cell response, enhancing anti-tumor efficacy.