Mapping B7-H3 Across the Tumour Microenvironment Reveals Vascular and Myeloid Compartments as Key Targets

A molecule once treated as a relatively obscure feature of cancer biology is moving toward the centre of the immuno-oncology conversation. B7-H3 (搜索)搜索该靶点, also known as CD276 (搜索)搜索该靶点, is attracting renewed attention because it appears across several compartments of the tumour microenvironment (TME) rather than being confined to malignant cells alone. A systematic review by Luisa Privitera, Paola Alberti, Silvia O. Senica and colleagues, published in the British Journal of Cancer, maps the reported presence of B7-H3 in stromal, vascular and immune components surrounding tumours. The work highlights why the protein has become one of the most closely watched targets in next-generation cancer research: its distribution may reveal not only where tumours hide from immune attack, but also how the tissue around them helps sustain disease.

The review included 31 original studies: one large multi-centre study with over 1,000 patients, 16 single-centre studies with more than 100 patients and 14 single-centre studies with fewer than 100 patients. No studies on paediatric solid tumours were identified in the search. B7-H3 (搜索)搜索该靶点 expression was most commonly assessed by immunohistochemistry, with flow cytometry predominantly used for immune compartment analyses. Significant heterogeneity was observed across studies, including differences in antibody selection, staining assessment and reporting, with some studies not specifying the antibody used.

B7-H3 in the Tumour Vasculature

Ten studies characterised B7-H3 (搜索)搜索该靶点 expression in the tumour-associated vasculature across different adult solid cancers. Across 2,963 tumour samples of different histologies, a total of 71% showed B7-H3 expression in tumour-associated blood vessels. Higher vascular B7-H3 expression was observed in several epithelial-derived tumours, including hepatocellular carcinoma, triple-positive breast cancer, pancreatic cancer, glioma and oesophageal squamous cell carcinoma, while triple-negative breast cancer (TNBC) also showed relatively high levels. Lower vascular expression was reported in less aggressive lesions, such as cervical intraepithelial neoplasia and in prostate and adrenal tumours.

Clear cell renal cell carcinoma (搜索)搜索该疾病 (ccRCC) represents the most robust vascular dataset in the review, with four studies and a total of 1,278 samples analysed by immunohistochemistry, of which 63% showed moderate to high expression, with consistent trends across studies (54–69% range). Specifically, Zhang et al. reported 67% high expression (n = 82), Inamura et al. observed 54% moderate-to-diffuse expression (n = 252), Qin et al. found approximately 69% moderate-to-diffuse expression (n = 200) and Crispen et al. noted about 63% moderate-to-diffuse expression (n = 744). No clear positive expression was detected in paired adjacent normal renal tissues or blood vessels.

Cervical carcinoma showed a more diverse pattern: cervical intraepithelial lesions mostly lacked B7-H3 (搜索)搜索该靶点 expression, with only 4% showing moderate to strong staining, whereas 80% of invasive squamous cell carcinomas had positive endothelial cells, with 14% exhibiting moderate and 66% displaying strong B7-H3 expression. Prostate and adrenal adenocarcinoma exhibited either no or low B7-H3 expression in the tumour-associated vasculature, with 63% and 52% of cases, respectively, showing negative B7-H3.

In Merkel cell carcinoma (MCC), Aung et al. combined multiplex immunofluorescence with a computational algorithm to analyse spatial colocalisation of B7-H3 (搜索)搜索该靶点 and the endothelial marker CD31. Out of 52 primary MCCs and 25 paired metastatic lesions, strong B7-H3 expression was often seen in tumour-associated endothelial cells, while vessels outside the tumour mass lacked this expression. Colocalisation of B7-H3 and CD31 in primary MCC correlated with increased vascular density, suggesting a potential association with tumour angiogenesis and local invasion, although this association was not observed in metastatic lesions.

Vascular Expression, Histopathology and Prognosis

The included studies suggest a link between B7-H3 (搜索)搜索该靶点 vascular positivity and microscopic malignant features. In ccRCC, higher B7-H3 levels in the tumour vasculature were associated with high nuclear grade, coagulative tumour necrosis and capsular invasion. High colocalisation between B7-H3 and CD31 in MCC was strongly linked to aggressive tumour characteristics, including increased invasion depth, larger tumour size and presence of lymphovascular invasion.

Several studies reported an association between B7-H3 (搜索)搜索该靶点 expression in tumour vasculature and poorer prognosis. In ovarian carcinomas, patients with B7-H3-positive vasculature had a 36% survival rate at 100 months post-diagnosis, compared to 65% in the B7-H3-negative group. Advanced ovarian carcinoma (FIGO stages III and IV) showed a 45% survival rate at 50 months, compared to an 80% survival rate in the B7-H3-negative group. In ccRCC, patients with widespread B7-H3 in tumour vasculature were nearly four times more likely to die from RCC than those with absent, focal, or moderate B7-H3 expression. In colorectal cancer (CRC), endothelial B7-H3 expression was also associated with reduced metastasis-free, disease-specific survival and overall survival.

However, vascular B7-H3 (搜索)搜索该靶点 expression has been associated with poorer survival only in a small number of tumour types, including ovarian carcinoma, ccRCC and CRC; therefore, its overall prognostic significance remains inconclusive. In adrenocortical and cervical carcinomas, no significant association between B7-H3 expression in the tumour vasculature and prognosis was observed.

B7-H3 in the Stromal Compartment

Ten studies evaluated B7-H3 (搜索)搜索该靶点 expression in the tumour-associated stroma across multiple solid tumours, including colorectal, ovarian, pancreatic, gastric, renal, cervical, lung and breast cancers. With the exception of TNBCs, the included studies generally reported over 50% positivity in stromal cells across the cancers examined. The highest positivity rates were found in cervical cancer, lung squamous cell carcinoma (SCC), pancreatic ductal adenocarcinoma (PDAC) and CRC.

Two studies focused exclusively on B7-H3 (搜索)搜索该靶点 expression in cancer-associated fibroblasts (CAFs) within CRC and RCC. In CRC, strong B7-H3 fibroblast expression was more common in rectal cancer samples (61.7%) than in colon cancer (48.8%). In RCC, flow cytometry revealed that 65.3% of CAFs expressed B7-H3 on the cell membrane. In ovarian cancer, researchers found that CD45-negative cells expressing stromal markers such as FAP and PDGFRβ exhibited significantly higher membranous levels of B7-H3 than epithelial cells, with CAFs representing the most prominent cell subtype.

Stromal B7-H3 (搜索)搜索该靶点 expression has been reported to associate with unfavourable histological features. Higher B7-H3 stromal expression in cervical cancers was linked to lymphovascular and lymph node invasion. In gastric cancer, stromal B7-H3 expression positively correlated with higher tumour stage, greater invasion depth and tumour phenotype. At a prognostic level, however, stromal B7-H3 expression has generally not been linked to adverse outcomes in most studies, with exceptions in TNBC and ovarian cancers, where high stromal B7-H3 expression was associated with poorer disease-free and overall survival.

B7-H3 in the Immune Compartment

Twelve papers quantified B7-H3 (搜索)搜索该靶点 expression within the tumour immune microenvironment. Most studies consistently showed higher B7-H3 expression in myeloid-derived immune cells, often associated with immunosuppressive phenotypes and tumour progression. In non-small cell lung cancer (NSCLC), B7-H3 was found on macrophages (20–95%), monocytes (10–80%), dendritic cells (10–90%), plasmacytoid dendritic cells (0–60%) and myeloid-derived suppressor cells (MDSCs: up to 100%). A prospective study confirmed B7-H3 expression on tumour-infiltrating monocyte/macrophages (64.34%), with nearly undetectable levels in adjacent normal tissues (5.88%).

A subset of CD14⁺HLA-DR⁻/low MDSCs expressing B7-H3 (搜索)搜索该靶点 made up to 30% of tumour-infiltrating MDSCs, with density decreasing with increasing distance from the tumour core. B7-H3-positive MDSCs were positively correlated with regulatory T cells (Tregs), consistent with the known role of MDSCs to induce Tregs. In pancreatic neuroendocrine neoplasms (PNEN), approximately 60–90% of tumour-associated macrophages (TAMs) express B7-H3, and TAMs are more numerous in cases with liver metastasis and associated with reduced T-cell infiltration.

Compared with myeloid populations, evidence in lymphoid cells remains more limited and less consistent. In colorectal cancers, about 45% of cases showed increased B7-H3 (搜索)搜索该靶点 levels in tumour-infiltrating lymphocytes (TILs), with an average B7-H3 expression ratio on infiltrating T cells notably higher (around 20%) compared to normal tissues (around 8%). High TIL B7-H3 expression was also observed in breast cancer patients, particularly in HER2-positive cases.

Implications for B7-H3-Directed Therapeutics

The findings have direct relevance for the rapidly expanding field of B7-H3 (搜索)搜索该靶点-directed therapeutics. Several strategies are being explored in cancer research, including monoclonal antibodies, antibody-drug conjugates, bispecific molecules and chimeric antigen receptor (CAR) T cells. CAR-T therapies and antibody-drug conjugates have demonstrated the greatest regulatory momentum, with intracerebroventricular B7-H3–targeted CAR-T therapy showing encouraging early results in diffuse intrinsic pontine glioma (搜索)搜索该疾病, and ifinatamab deruxtecan查看药品详情 advancing into phase III evaluation for small-cell lung cancer (搜索)搜索该疾病 (SCLC).

In most of these trials, patient selection remains largely based on tumour cell B7-H3 (搜索)搜索该靶点 positivity, with limited consideration of compartment-specific expression within the TME. The review's findings suggest this may be an area for further investigation, particularly to understand whether non-tumour cell expression contributes to therapeutic response or resistance.

The authors acknowledge key limitations. There is significant heterogeneity among studies regarding design, detection techniques, scoring methods and patient populations. Most studies are single-centre, limiting the ability to compare results and generalise findings broadly. Many studies rely on univariate analyses that do not account for tumour grade, stage, or treatment, so observed associations may reflect tumour aggressiveness rather than direct effects of B7-H3 (搜索)搜索该靶点. While several paediatric cancers are known to express B7-H3 at the tumour cell level, studies assessing its distribution across TME compartments were not identified, highlighting an important gap given the growing interest in B7-H3 as a therapeutic target in paediatric oncology.

The review concludes that tumour-associated vasculature and myeloid-derived cells are key B7-H3 (搜索)搜索该靶点-positive compartments within the TME. However, further studies incorporating standardised methodologies and more comprehensive analyses are needed to determine whether targeting B7-H3 in distinct TME compartments can meaningfully modulate tumour progression or improve therapeutic outcomes.