B7-H3: Role in Immune Function and Pathology

B7-H3 is an immune checkpoint molecule that modulates immune responses. Initially thought to be co-stimulatory, emerging evidence suggests it primarily exerts immunosuppressive effects on both innate and adaptive immunity. Its role extends beyond normal immune regulation to various pathological conditions, particularly cancer, where it contributes to immune evasion.

Understanding B7-H3’s molecular characteristics, functional roles, and expression patterns provides insight into its significance in disease progression and potential as a therapeutic target.

Molecular Structure

B7-H3, also known as CD276, is a type I transmembrane glycoprotein in the B7 family of immune regulatory molecules. It shares structural homology with other B7 members, particularly in its extracellular domain, which consists of immunoglobulin-like (Ig) domains. The human protein exists in two primary isoforms: a two-Ig domain form (2Ig-B7-H3) and a four-Ig domain variant (4Ig-B7-H3), with the latter being predominant in humans. This structural distinction influences its functional interactions, while the two-Ig domain form is more common in murine models.

The extracellular region is responsible for ligand binding, but its receptor remains unidentified. Unlike PD-L1 and CTLA-4, which have well-characterized binding partners, B7-H3’s signaling mechanisms are not fully understood. Structural analyses suggest the four-Ig domain form enhances ligand engagement, influencing downstream signaling. Glycosylation patterns further modulate its stability and interactions.

The transmembrane region anchors B7-H3 to the cell membrane, facilitating its localization within lipid rafts—specialized microdomains involved in signal transduction. This positioning may affect its interactions with other membrane-bound proteins. The intracellular domain is relatively short and lacks known signaling motifs, indicating its function is primarily mediated through extracellular interactions. However, emerging evidence suggests it may participate in signal transduction indirectly by associating with adaptor proteins or co-receptors.

Role In Immune Function

B7-H3 modulates immune responses by limiting T cell activation and dampening pro-inflammatory responses. It inhibits T cell proliferation and cytokine production, particularly downregulating IFN-γ and IL-2, which are critical for sustaining immune responses. This suppression fosters an immune landscape that favors tolerance and reduced cytotoxic activity.

Beyond cytokine suppression, B7-H3 interferes with CD4+ and CD8+ T cell function by modulating co-stimulatory and co-inhibitory signaling pathways. It impairs CD8+ T cell differentiation and cytotoxic potential, inducing anergy, a state of functional unresponsiveness despite antigen recognition. Additionally, it skews CD4+ T cells away from Th1 differentiation while promoting regulatory T cell (Treg) expansion, reinforcing an immunosuppressive environment.

B7-H3 also affects innate immunity, particularly natural killer (NK) cells and antigen-presenting cells. It dampens NK cell-mediated cytotoxicity by impairing activation and reducing granzyme B and perforin expression, molecules essential for NK cell-mediated lysis. This inhibition can hinder immune surveillance against malignant or infected cells. It also modulates dendritic cell function, altering cytokine secretion and influencing antigen presentation, further reinforcing immune suppression.

Expression Patterns

B7-H3 expression varies across tissues and cell types. Under physiological conditions, it is relatively low, primarily localized to antigen-presenting cells, endothelial cells, and certain epithelial cells. Its expression can be upregulated in response to inflammatory signals and microenvironmental changes, indicating dynamic regulation.

Its expression is controlled at multiple levels, including transcriptional, post-transcriptional, and post-translational mechanisms. Transcription factors such as Sp1 and AP-2 influence gene expression, while microRNAs like miR-29 and miR-124 contribute to post-transcriptional repression. Epigenetic modifications, including histone acetylation and DNA methylation, further regulate its variability.

B7-H3 is markedly upregulated in malignancies, including lung, breast, prostate, and melanoma cancers. Oncogenic signaling pathways like STAT3 and NF-κB drive this overexpression. Tumor-associated stromal cells, including cancer-associated fibroblasts and endothelial cells, also exhibit elevated B7-H3 expression, contributing to a tumor-supportive microenvironment. This widespread overexpression has made it a target for diagnostic and therapeutic approaches.

Relationship With PD-L1

B7-H3 and PD-L1 share functional similarities in immune evasion but operate through distinct mechanisms. While PD-L1 suppresses T cell activity by interacting with PD-1, B7-H3 lacks a confirmed receptor, complicating direct comparisons. However, their concurrent overexpression in cancers suggests complementary roles in immune suppression. Some malignancies exhibit high levels of both, while others preferentially upregulate B7-H3, particularly in tumors resistant to PD-1/PD-L1 therapies.

This differential expression has therapeutic implications. Patients who fail to respond to PD-1/PD-L1 blockade often exhibit persistent B7-H3 expression, indicating a compensatory mechanism sustaining immune suppression. Preclinical models show that dual inhibition of B7-H3 and PD-L1 enhances anti-tumor responses compared to targeting either molecule alone. This has led to the development of combination therapies, including monoclonal antibodies and antibody-drug conjugates, aimed at overcoming resistance.

Associations With Pathological Conditions

B7-H3 is implicated in various pathological conditions, including cancer, inflammatory disorders, autoimmune diseases, and neurological conditions. Its ability to modulate immune responses and influence cellular signaling makes it a key factor in disease progression.

In oncology, B7-H3 is overexpressed in solid tumors such as lung, breast, prostate, and colorectal cancers, correlating with poor prognosis, increased metastatic potential, and resistance to immunotherapy. High B7-H3 expression is associated with tumor proliferation, angiogenesis, and epithelial-to-mesenchymal transition (EMT), processes that facilitate invasion and metastasis. It interacts with oncogenic signaling pathways like STAT3 and PI3K/AKT, promoting tumor survival and immune escape. Clinical data link elevated B7-H3 levels to reduced survival and increased tumor aggressiveness, underscoring its value as a prognostic biomarker. Its expression in tumor vasculature and stromal cells further shapes the tumor microenvironment.

Beyond cancer, B7-H3 is linked to chronic inflammatory diseases like rheumatoid arthritis and inflammatory bowel disease, where its elevated expression in affected tissues contributes to persistent inflammation. In neurological disorders such as multiple sclerosis and glioblastoma, B7-H3 modulates microglial activation and neuroimmune interactions, potentially influencing neuronal survival and immune-mediated neurodegeneration. These diverse associations highlight its complexity in disease, reinforcing the need for targeted therapeutic strategies.

Laboratory Techniques For Detection

Detecting and quantifying B7-H3 in clinical and research settings requires precise methodologies to assess its expression at both protein and transcript levels. These methods are particularly relevant in oncology, where B7-H3 serves as a biomarker for prognosis and a potential therapeutic target.

Immunohistochemistry (IHC) is widely used to detect B7-H3 in tissue samples, providing spatial localization within tumors and surrounding stromal compartments. Antibody-based staining allows pathologists to assess expression intensity and correlate it with clinical outcomes. Flow cytometry evaluates B7-H3 expression on immune and tumor cells in liquid biopsies, offering quantitative single-cell analysis.

Molecular techniques such as quantitative PCR (qPCR) and RNA sequencing measure B7-H3 mRNA levels, providing insights into its transcriptional regulation. Western blotting and enzyme-linked immunosorbent assays (ELISA) detect B7-H3 in tissue lysates and serum samples, expanding its potential as a non-invasive biomarker. Emerging technologies, including mass spectrometry-based proteomics and single-cell RNA sequencing, further refine B7-H3 characterization with greater specificity and resolution. Integrating these methods enhances its utility in both research and clinical applications.