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High B7-H3 protein expression in Medulloblastoma is associated with metastasis and unfavorable patient outcomes

Diagnostic Pathology volume 20, Article number: 49 (2025) Cite this article

Abstract

Background

Medulloblastoma (MB) is the most common malignant brain tumor in children. Although the 5-year survival rate is approximately 70–80%, the current standard treatment results in severe and long-term side effects. The search for new anticancer immunotherapeutic targets has identified B7-H3 as a promising candidate in various solid tumors. However, the role of B7-H3 in MB remains unclear, and studies reporting its protein expression and association with clinicopathological characteristics are still limited.

Methods

In this study, B7-H3 protein expression was evaluated by immunohistochemistry in seven non-tumor samples and 43 molecularly characterized MB tissues. Its expression profile was correlated with B7-H3 (CD276) mRNA levels, which were previously determined by nCounter, as well as with the patients’ clinical features.

Results

Only 14.3% (1/7) of non-tumor brain and cerebellum tissues showed B7-H3 positivity, whereas 95.6% (41/43) of the MB samples expressed this protein at distinct levels. B7-H3 was found in the cytoplasm and on the membrane of cancer cells. A significant positive correlation was observed between CD276 mRNA and B7-H3 protein levels. Moreover, high expression of B7-H3 protein was associated with worse overall survival and the presence of metastasis at diagnosis.

Conclusions

This is the first study to associate CD276 mRNA and B7-H3 protein levels in MB, revealing a significant positive correlation. We observed that B7-H3 was overexpressed in MB compared to non-tumor brain tissue. High B7-H3 expression was associated with a worse outcome and with the presence of metastasis at diagnosis.

Background

Medulloblastoma (MB), an embryonal tumor of the cerebellum, is the most common malignant brain tumor in children, with a minority of the cases occurring in adulthood [1]. It is classified by the World Health Organization (WHO) as a grade 4 malignancy and divided into four principal molecular subgroups, WNT, SHH, Group 3, and Group 4, that exhibit distinct clinical and prognostic features [2, 3, 4, 5]. The current standard of care involves maximum safe surgical resection, craniospinal radiation, and chemotherapy, with a 70–80% 5-year survival rate [1]. Unfortunately, many patients suffer from severe, lifelong side effects, namely neurocognitive, neuroendocrine, and psychosocial deficits [1, 6]. Therefore, safer and more effective therapies for MB patients represent an unmet clinical need.

Immunotherapy has emerged as a promising alternative in anticancer treatment [7, 8]. However, the most commonly used immunotherapies, such as those targeting CTLA-4 and the PD-1/PD-L1 axis, have been disappointing in MB, similar to other central nervous system (CNS) tumors. This is partly explained by the usually low tumor mutational burden (TMB), immune cell infiltration, and negative/low expression of immunotherapy targets in brain tumors [9, 10]. Recently, our group evaluated the mRNA immune checkpoint (IC) profile in a large cohort of MB patients [11]. We showed the absence or low expression of the canonical ICs PD-L1 (at both mRNA and protein levels), CTLA4, and PDCD1 [11]. Importantly, we identified the overexpression of CD276 (B7-H3) in MB compared to non-tumor tissues, especially in WNT and Group 4 [11]. Furthermore, our in silico analysis showed that high CD276 levels were associated with worse overall survival (OS) in these molecular subgroups [11].

The B7 homolog 3 (B7-H3) protein, encoded by the CD276 gene, is a multifunctional protein member of the B7 family of immunoglobulins, which has been gaining interest in immuno-oncology field [12, 13]. B7-H3 has an immunoregulatory role, inhibiting T- and NK-cell activity and promoting macrophage polarization toward an M2 phenotype [12, 13]. Beyond its immunoregulatory role, B7-H3 has also been associated with several tumorigenic properties, such as epithelial-to-mesenchymal transition (EMT), decreased apoptosis, cell cycle arrest, glycolytic metabolism, angiogenesis, metastasis, and chemoresistance, through the JAK2/STAT3, MMP-2/9, VEGFA, PI3K/AKT/mTOR and ERK/MAPK oncogenic pathways [10, 12, 13]. In line with this, B7-H3 has been described as a pan-cancer antigen, highly expressed across various tumor types compared to normal tissues, and associated with higher tumor stages and poor prognosis in several malignancies, mainly in adult tumors [12, 14, 15, 16]. Although less investigated in pediatric CNS and extra-CNS solid tumors, B7-H3 has also been found to be highly expressed [16, 17]. Reports on B7-H3 protein expression in MB are limited.

Our study aimed to assess the expression pattern of B7-H3 protein in a previously molecularly characterized cohort of MB patients and evaluate its correlation with the mRNA levels of CD276. Moreover, we investigated its potential as a prognostic biomarker.

Methods

Patients

A total of 43 MB samples were used in this retrospective study (Table 1). The samples were collected from patients diagnosed at Barretos Cancer Hospital (BCH) in Barretos, Brazil (n = 37), and the Federal University of São Paulo (UNIFESP) (n = 6), Brazil, from 1996 to 2018. The molecular subgrouping of the cases was performed using a previously reported nCounter assay method employing a 22-gene set and formalin-fixed paraffin-embedded (FFPE) tissue [18]. The tumors were classified as WNT (n = 6, 14%), SHH (n = 21, 48.8%), Group 3 (n = 4, 9.3%), and Group4 (n = 12, 27.9%) (Table 1) [18]. All cases had their CD276 mRNA levels previously analyzed with the nCounter® FLEX Analysis System using the PanCancer Immune Profiling Panel (NanoString Technologies, Inc.) [11]. Additionally, seven non-tumor samples derived from non-tumor tissue surrounding brain metastasis were evaluated. Both tumor and non-tumor tissues were fixed in 3.7% formaldehyde for 24 to 48 h. This study was approved by the Research Ethics Committee at Barretos Cancer Hospital (Project #1248/2016).

Table 1 Clinicopathological characteristics of the 43 MB patient’s cohort
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B7-H3 immunohistochemistry (IHC)

Representative 4 µm-thick FFPE tissue sections were subjected to immunohistochemical analysis according to the streptavidin-biotin peroxidase complex system (UltraVision Plus Detection System: Large Volume Anti-Polyvalent, HRP, catalog no. TP-125-HLX, LabVision Corporation). Briefly, deparaffinized and rehydrated slides were submitted to heat-induced antigen retrieval for 20 minutes at 98°C, and 4 minutes at 120°C with 1 mM tris(hydroxymethyl)aminomethane (Tris)–ethylenediaminetetraacetic acid (EDTA) buffer (pH 7.8), using a pressure chamber (DakoCytomation Pascal S2800, Dako). Subsequently, endogenous peroxidase activity was blocked using 3% hydrogen peroxide (H2O2) in methanol, and the tissues were then incubated with Ultra V block (LabVision Corporation). Slides were then incubated with the anti-B7-H3 primary antibody (catalog no. AF1027, R&D systems, dilution 1:200) and then with the biotinylated secondary antibody (catalog no. 705-065-003, Jackson ImmunoResearch, dilution 1:1000) for 30 minutes at room temperature as described [19, 20]. Afterward, slides were treated with streptavidin labeled horseradish peroxidase (HRP) and subsequently incubated with the chromogen 3,3’-diaminobenzidine (DAB, Dako Liquid DAB + Substrate Chromogen System, catalog no. K3468, Dako) for 10 min, followed by counterstaining with hematoxylin and dehydration. Colorectal adenocarcinoma and CNS breast metastasis tissues served as positive controls. Negative controls included reactions without the primary antibody.

The reactions were analyzed in a blinded manner by an expert neuropathologist (GRT) using a two-score system, as follows: score of intensity (0, negative; 1, weak; 2, medium; and 3, strong) and score of extension (0, negative; 1, ~ 25% of cells stained; 2, between 25% and 50%; and 3, more than 50% of cells stained). The two scores were summed, with expression levels classified as low/moderate (sum between 0 and 4) or high (sum above 5). The cellular localization of B7-H3 was also recorded for each sample. Representative images were obtained with an Olympus BX53 microscope and a DP74 digital camera using Cell P software.

Statistical analysis

Data visualization and statistical analysis were conducted using Prism 8.0 (GraphPad Software), R (version 4.4.1) with ggsurvplot, and IBM SPSS version 29.0 (SPSS Inc.). Data were presented as median and interquartile range (IQR) or mean and standard error of the mean (SEM) when indicated. The difference in B7-H3 protein scores between MB samples from the different molecular subgroups and non-tumor tissue was analyzed using the Kruskal-Wallis test.

For survival analysis based on B7-H3 expression (low/moderate vs. high), the event was defined as cancer-related death, with overall survival (OS) as the outcome endpoint, measured from the date of diagnosis to death or the last follow-up. Survival rates were plotted using the Kaplan-Meier method, and associations with B7-H3 expression were analyzed with the log-rank test. For this and subsequent analysis relapse samples were excluded due to distinct biological and clinical differences between relapsed and primary tumors, which makes direct comparisons inappropriate. The association between B7-H3 expression and the clinical data of the patients was examined using the chi-square test (χ2-test).

To compare the mean CD276 mRNA counts [11] of B7-H3 low/moderate and high expression groups of patients, an independent samples student t-test was employed. The association between CD276 mRNA and B7-H3 protein score was performed using Pearson correlation.

Univariate and multivariate analyses were conducted using the Cox regression model (proportional hazards). Statistical significance for all analyses was set at p ≤ 0.05.

Results

Characterization of B7-H3 expression in Medulloblastoma

We evaluated B7-H3 protein expression by IHC in a series of 43 MBs with CD276 mRNA levels previously analyzed at the transcriptomic level using a 770 immune-oncology-related genes panel [11]. Additionally, seven non-tumor brain/cerebellum samples were also analyzed.

We found that only one of seven (14.3%) of the non-tumor tissues depicted B7-H3 expression in brain parenchyma, with the majority being negative (Fig. 1A and B). In contrast to non-tumor tissue, membranous B7-H3 expression was detected in a brain metastasis from a patient with breast adenocarcinoma (Fig. 1C). Furthermore, 41 of 43 (95.3%) MB cases depicted positive B7-H3 expression, predominantly localized in the cytoplasm of neoplastic cells (Fig. 1D). Additionally, 14 of 41 (34.1%) cases exhibited both membranous and cytoplasmic expression (Fig. 1E and F).

Fig. 1
figure 1

Immunohistochemistry analysis of B7-H3 in MB and non-tumor samples. (A and B) Non-tumor cerebellum with negative B7-H3 expression (100X and 200X magnification, respectively). (C) Membranous expression on a brain metastasis from a breast metastatic adenocarcinoma (400X magnification). (D) MB weak cytoplasmic expression (400X magnification). (E) and (F) MB strong cytoplasmic and membranous expression (400X magnification)

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Upon analyzing B7-H3 scores in non-tumor samples (median score 0 ± 0) and the four molecular subgroups of MB, we found that it was significantly overexpressed in tumors compared to non-tumor cases (Fig. 2). However, no differences in protein expression levels were observed among the four molecular subgroups, with median scores of 4 ± 2.5, 4 ± 2, 2 ± 3, and 3.5 ± 2.5 for WNT, SHH, Group 3, and Group 4, respectively (Fig. 2).

Fig. 2
figure 2

B7-H3 score across the molecular subgroups of MB. Group comparisons were performed using Kruskal-Wallis test (H = 19.62, df = 5, p = 0.0006). For pairwise post hoc comparisons, Dunn’s test was applied, and a significant increase of B7-H3 scores was observed in WNT, SHH and Group 4 MB compared to non-tumor tissue (p = 0.0161, p = 0.0004 and p = 0.0147, respectively). P-values are graphically represented as follows: p > 0.05, ns; *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.001; and ****p ≤ 0.0001

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B7-H3 expression was detected in some immune cells in non-tumor samples (data not shown); however, in MB samples, its expression appeared to be restricted to neoplastic cells.

Association of B7-H3 protein and patients clinicopathological features

B7-H3 protein expression was elevated in MB compared to non-tumor samples, consistent with previous reports [16, 17, 20, 21, 22]. However, prior studies primarily examined its relationship with immune cell infiltration without assessing its association with standard clinicopathological characteristics [21]. Therefore, we further investigated the association between B7-H3 expression and clinicopathological features in 41 primary MBs (Table 2). Notably, as already mentioned, the two relapse cases were excluded from all subsequent analyses due to biological and clinical differences (Table 1). High B7-H3 expression, defined as a total score of intensity and extent above 5, was significantly associated with the presence of metastasis at diagnosis (χ2-test, p = 0.050), with no other significant associations being observed.

Table 2 Association of B7-H3 expression with clinicopathological data and with CD276 mRNA
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Additionally, we evaluated the relationship between B7-H3 protein and CD276 mRNA levels (Table 2). Patients with high B7-H3 expression exhibited significantly higher CD276 mRNA mean counts compared to those in the low/moderate expression group (independent samples Student’s t-test: t(41) = ‒2.299, p = 0.027). A weak but statistically significant positive correlation was observed between CD276/B7-H3 mRNA and protein levels in our cohort (Pearson’s r = 0.336, p = 0.032) (Table 2).

B7-H3 protein overexpression is associated with lower overall survival and the presence of metastasis at diagnosis

Lastly, we evaluated the impact of B7-H3 protein expression on the OS of MB patients using the Kaplan-Meier method. Patients with high B7-H3 expression had a lower survival probability than those with low/moderate expression (Fig. 3A). The median survival time for patients with high B7-H3 expression was 83.7 months (95% CI: 3.9–163.5), whereas patients with low/moderate B7-H3 expression did not reach the median survival time during the follow-up, with over 50% of patients remaining alive at the last follow-up (Table 2). For comparative purposes, the mean OS was 100.6 in the high expression group versus 187.1 months in the low/moderate group (Table 3).

Fig. 3
figure 3

Overall survival according to B7-H3 expression in MB. (A) MB patients (n = 41) were categorized into two groups according to B7-H3 expression levels: low/moderate and high. OS probabilities were estimated using the Kaplan-Meier method, and survival distributions were compared via the log-rank test (χ² = 6.791, df = 1, p = 0.009). High B7-H3 expression was significantly associated with shorter OS. The median survival time for patients with high B7-H3 expression was 83.7 months (95% CI: 3.9-163.5), whereas the median survival time for patients with low/moderate B7-H3 expression was not reached during the follow-up period. (B) Patients were further stratified based on B7-H3 cellular localization (cytoplasm only vs. cytoplasmic/membranous expression). In the two subgroups, high B7-H3 expression was associated with lower survival probabilities. However, a significant association with a worse OS was observed only in patients with cytoplasmic/membranous B7-H3 expression (log-rank test: χ² = 4.046, df = 1, p = 0.044)

Full size image

Considering B7-H3’s known role as an IC, we evaluated B7-H3 cellular expression and its potential impact on survival. We found no significant association between B7-H3 cellular localization and protein expression levels (Table 2). Furthermore, when analyzing the effect of protein levels on survival based on cellular localization, we observed that, regardless of localization, patients with high B7-H3 expression exhibited a trend toward lower OS (Fig. 3B).

Lastly, a univariate analysis revealed that high B7-H3 expression, partial surgical resection, and the presence of metastasis at diagnosis were associated with an increased risk of death by 3.2, 2, and 2.1-fold, respectively, compared to patients with low/moderate B7-H3 expression, who underwent complete tumor resection, and those without metastasis at diagnosis (Table 3). However, in the multivariate Cox proportional hazards model, none of these variables achieved statistical significance as independent predictors of OS (Table 3).

Table 3 Cox regression analysis
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Discussion

Our group recently reported that CD276, the gene encoding B7-H3, is among the most highly expressed ICs in MB and was associated with worse patient outcomes, particularly in the WNT and Group 4 subtypes [11]. In this study, using a subset of the previous analyzed cohort, we evaluated whether B7-H3 protein expression was also elevated, whether it correlated with mRNA levels and whether it could have a clinical impact.

First, we observed that B7-H3 is virtually absent in the non-tumor brain and cerebellar tissues, which was consistent with previous reports [16, 19, 23]. At variance, 95.6% (41/43) of MB cases exhibited B7-H3 positivity, demonstrating a statistically significant increase in tumor samples compared to the non-tumor tissues. No significant difference in B7-H3 protein levels were observed across the molecular subgroups. These findings align with prior studies using different anti-B7-H3 antibodies, which reported positivity rates ranging from 96 to 100% [16, 17, 20, 21, 22], with some authors describing a predominant expression in Group 4 MB [21].

Furthermore, we found a significant weak positive correlation between CD276/B7-H3 mRNA and protein levels in MB. Our results are in accordance with previous studies that reported a positive correlation between mRNA and protein levels of CD276/B7-H3 in prostate cancer cell lines and patient-derived xenografts [14] and in other CNS malignancies as well [17]. These findings suggest that B7-H3 protein expression could serve as a proxy for CD276 mRNA levels, providing a cost-effective alternative to CD276 expression analysis while also enabling cellular localization assessment. Nevertheless, given that RNA-based assays are widely used for MB molecular classification, as we and others previously described [24, 25, 26], integrating CD276 mRNA quantification into routine assays could facilitate a more comprehensive understanding of B7-H3’s role in MB tumorigenesis.

Notably, few studies have interrogated the association of B7-H3 protein expression in MB with clinicopathological characteristics, and none of them performed survival analyses [16, 17, 20, 21, 22]. In our cohort, high B7-H3 expression was associated with the presence of metastasis at diagnosis, compared to those with low/moderate expression. This suggests a potential role of B7-H3 in MB progression and dissemination. Additionally, we found that patients with high B7-H3 expression experienced significantly poorer OS, suggesting that this protein may serve as a prognostic factor in MB. However, in our multivariate model, B7-H3 expression did not independently predict survival after adjusting for other clinical variables. This finding underscores the need for larger, statistically powered studies to clarify its value as an independent prognostic biomarker.

B7-H3 is increasingly recognized for its role in pediatric brain tumors [16, 17, 19, 20, 21, 22]. In pediatric gliomas and ependymomas, higher B7-H3 expression levels have been linked to higher WHO grades [16]. In MB, B7-H3 protein was found to be more highly expressed in Group 4, while the lowest levels were observed in the SHH subgroup [17, 21]. Additionally, B7-H3 expression was associated with reduced infiltration of γδT and CD3 + T cells, suggesting a potential role in immune evasion [21].

Furthermore, regarding B7-H3 cellular localization, we observed that most MB samples displayed solely cytoplasmic expression, while a subset exhibited both cytoplasmic and membranous staining. Previous reports have detected B7-H3 in the cytoplasm, membrane, and nucleus [13, 27], though in most solid tumors, membranous expression was predominant, with only a minority reporting cytoplasmic localization [27, 28, 29, 30]. To determine whether B7-H3 localization impacted prognosis, we conducted survival analyses stratified by cellular localization. We observed a trend toward poorer OS in patients with high B7-H3 expression, regardless of localization. However, statistical significance was reached only when B7-H3 was expressed in both cytoplasm and membrane. To our knowledge, this is the first study to report predominantly cytoplasmic B7-H3 expression in MB, suggesting a potential functional role beyond immune modulation.

While we highlight the importance of B7-H3 in MB, the mechanisms underlying its overexpression and role in tumor biology remain unclear. Experimental studies have shown that CD276 genetic inhibition reduces cell migration and invasion in vitro [23], and B7-H3 has been implicated in angiogenesis and exosome production [31, 32]. In Group 3 MB, MYC and EZH2 have been implicated in B7-H3 regulation [32, 33], while microRNAs such as miR-29 and miR-1253 have also been identified as potential regulatory elements [23, 32]. These findings highlight the complexity of B7-H3 biology and suggest multiple avenues for therapeutic intervention. Given its tumor-specific overexpression and correlation with aggressive disease phenotypes, B7-H3 represents a promising target for therapeutic intervention. In fact, emerging evidence suggests that B7-H3-targeting strategies could be effective in MB [20, 34]. Future studies should explore B7-H3-directed therapies, including monoclonal antibodies, CAR-T cell therapy, and antibody-drug conjugates, to assess their potential clinical benefit in MB patients.

Conclusions

In conclusion, we characterized B7-H3 protein expression in a previously characterized MB cohort and confirmed its overexpression in tumors compared to non-tumor brain/cerebellum tissues. Our findings suggest that B7-H3 is associated with the presence of metastasis at diagnosis and poor outcome, supporting its potential as a marker of aggressive disease. Future studies with larger patient cohorts and mechanistic investigations are needed to further define B7-H3’s role in MB biology and its therapeutic potential.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

CI:

Confidence interval

CNS:

Central nervous system

FFPE:

Formalin-fixed paraffin-embedded

HR:

Hazard ratio

IC:

Immune checkpoint

IHC:

Immunohistochemistry

MB:

Medulloblastoma

OS:

Overall survival

SEM:

Standard error of the mean

WHO:

World Health Organization

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Funding

This study was supported by was supported by Brazilian Ministry of Health (MoH), National Council for Scientific and Technological Development - CNPq, Brazil, and Brazilian National Program of Genomics and Precision Health – Genomas Brasil (MS-SECTICS-Decit/CNPq n° 16/2023- INOVACRIANÇA - Inovação terapêutica em crianças com tumores sólidos: uma jornada de precisão). PF is a recipient of a FCT PhD fellowship (2021.07647.BD), DAM of a DTI-A MS-SECTICS-Decit/CNPq n° 16/2023 fellowship, RFM is a recipient of a Fundação Rui Osório de Castro Master fellowship and RMR is a recipient of a CNPq Productivity (Brazil) fellowship.

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Authors and Affiliations

  1. Molecular Oncology Research Center, Barretos Cancer Hospital, Rua Antenor Duarte Vilela, 1331, Barretos, SP, 14784-400, Brazil

    Patrícia Fontão, Daniel Antunes Moreno, Bruna Minniti Mançano & Rui Manuel Reis

  2. Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal

    Patrícia Fontão, Rui Ferreira Marques & Rui Manuel Reis

  3. ICVS/3Bs-PT Government Associate Laboratory, Braga/Guimarães, Portugal

    Patrícia Fontão, Rui Ferreira Marques & Rui Manuel Reis

  4. Barretos School of Health Sciences, Dr. Paulo Prata – FACISB, Barretos, São Paulo, Brazil

    Gustavo Ramos Teixeira

  5. Department of Pathology, Barretos Cancer Hospital, Barretos, São Paulo, Brazil

    Gustavo Ramos Teixeira

  6. Federal University of São Paulo, São Paulo, Brazil

    João Norberto Stavale & Suzana Maria Fleury Malheiros

  7. Barretos Children’s Cancer Hospital, Barretos, Brazil

    Carlos Almeida Júnior

Authors
  1. Patrícia Fontão
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  2. Gustavo Ramos Teixeira
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  3. Daniel Antunes Moreno
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  4. Rui Ferreira Marques
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  5. João Norberto Stavale
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  6. Suzana Maria Fleury Malheiros
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  7. Carlos Almeida Júnior
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  8. Bruna Minniti Mançano
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  9. Rui Manuel Reis
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Contributions

RMR was responsible for the study concept, designed and supervised the work. PF performed the IHC reactions, the statistical analysis, updated the patient’s data and drafted the manuscript. GRT reviewed all IHC optimizations and scored the slides. DAM organized the patient database and contributed with preliminary optimizations of the IHC reactions. RFM organized the patient database and the CD276 mRNA counts data from the previous study. JNS and SMFM contributed with the UNIFESP MB samples and organized their data to include in the patient database. CAJ and BMM analyzed the medical reports. All authors were involved in the discussion of the results, have reviewed and approved the manuscript.

Corresponding author

Correspondence to Rui Manuel Reis.

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Ethics approval and consent to participate

This study was reviewed and approved by the Ethics Committee in Research from Barretos’ Cancer Hospital (Project #1248/2016).

Competing interests

The authors declare no competing interests.

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Fontão, P., Teixeira, G.R., Moreno, D.A. et al. High B7-H3 protein expression in Medulloblastoma is associated with metastasis and unfavorable patient outcomes. Diagn Pathol 20, 49 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13000-025-01645-y

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13000-025-01645-y

Keywords

Diagnostic Pathology

ISSN: 1746-1596

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