Survival and clinicopathological significance of B7-H3 in bladder cancer: a systematic review and meta-analysis

Bladder cancer (BC) is a common cancer of the urinary tract, with an estimated 573,278 new cases and 212,536 deaths annually worldwide [1]. The disease is clinically classified into nonmuscle invasive bladder cancer (NMIBC)(Ta/T1) and muscle-invasive bladder cancer (MIBC)(T2-T4), based on different clinical progressions and prognoses. Despite advancements in current therapeutic methods, including surgery, radiation therapy, and chemotherapy, the 5-year overall survival (OS) rate remains unsatisfactory, particularly for advanced bladder cancer [2‐4]. Therefore, finding a novel biomarker as an effective therapeutic target to improve the prognosis of bladder cancer patients is crucial.

Bladder cancer (BC) has been extensively studied for prognostic markers [5‐9]. CTCs have emerged as potential prognostic markers in various cancers [10‐12], including BC [13], but their detection and enrichment present challenges due to their scarcity and molecular heterogeneity [9]. FGFR3 mutation status is also linked to clinical prognosis, with better survival rates observed in patients with the FGFR3 mutation [14, 15]. However, agents targeting FGFR3 mutation are still in early clinical experiments, and their efficacy and safety remain uncertain [16‐18]. Additionally, HER2 status has been associated with higher stage and grade and poor disease-specific survival, particularly in muscle-invasive and metastatic BC [19, 20]. However, HER2’s prognostic role in non-muscle-invasive BC is more debatable [8, 21]. Given these limitations and uncertainties, there is a need for improved prognostic biomarkers in BC to enhance clinical management and treatment decisions.

B7-H3 (CD276) belongs to the B7 superfamily of molecules and shows potential as a promising target for cancer treatment. The expression of the B7-H3 protein has been observed in various tumor tissues, including non-small cell lung cancer (NSCLC) and prostate cancer, and it is closely associated with tumor progression, metastasis, recurrence, and other adverse clinical features [22‐27]. Its prognostic impact has been established in certain solid tumors, including clear cell renal cell carcinoma, breast cancer, and gastric cancer [28‐30]. While several studies have explored the connection between bladder cancer and B7-H3 expression, the clinical-pathological and prognostic significance of B7-H3 in bladder cancer remains uncertain.

This meta-analysis adhered to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines. The protocol for the overarching project has been published and registered with PROSPERO (registration No. CRD42022364688).

Bladder cancer (BC) represents a global health challenge with high morbidity and mortality rates [1]. Despite the advancements in biotechnology, numerous prognostic markers have been identified for bladder cancer; however, each comes with its own set of limitations [13, 15, 21]. Consequently, there is an imminent demand for the identification of a superior marker.

B7-H3, also known as CD276, belongs to the B7 family of immune checkpoint proteins. It is an immunoglobulin type I transmembrane protein composed of 316 amino acids. In humans, it is encoded by chromosome 15q24 and consists of an extracellular structural domain, a transmembrane structural domain, and a short intracellular tail [40]. While B7-H3 mRNA is expressed in most normal tissues, B7-H3 protein is either not expressed or expressed at very low levels in normal tissues [41, 42]. However, it is highly expressed in various cancer cells, including breast [43], lung [44], and ovarian cancers [45]. With the advancement of research, accumulating evidence has highlighted a strong association between B7-H3 and the initiation and progression of different cancers. Aberrant B7-H3 expression has been implicated in influencing multiple cellular processes, such as migration, invasion, chemoresistance, endothelial-to-mesenchymal transition, and tumor cell metabolism [26, 46‐51]. Furthermore, several studies [24, 27, 52, 53] have reported that patients with elevated tumor B7-H3 levels experienced shorter survival times.

The role of B7-H3 in the prognosis and clinicopathological features of bladder cancer (BC) has been investigated in several studies, but the results have shown inconsistencies [33, 35, 36, 38]. Therefore, we conducted this meta-analysis, including eight articles encompassing a total of 1622 patients. Our findings indicated that B7-H3 expression was not associated with a poor prognosis in BC patients, while B7-H3 expression levels were higher in BC patients compared to normal tissues. In addition to investigating the prognostic aspect, we also analyzed the relationship between B7-H3 and clinicopathological features of BC. The results revealed a significant association between high B7-H3 expression and age, tumor infiltration, and recurrence. However, no significant relationship was observed between B7-H3 and other clinical characteristics. It is worth noting that our data did not support the idea that B7-H3 expression predicts poor survival in bladder cancer. This discrepancy may be attributed, in part, to the limited total sample size in our meta-analysis, which could introduce bias.

Currently, the mechanisms underlying B7-H3’s role in tumorigenesis and development remain unclear. However, several potential mechanisms have been proposed. Firstly, B7-H3 affects tumor cell metabolism, as evidenced in triple-negative breast cancer where decreased B7-H3 expression reduces tumor cell glycolytic capacity and increases sensitivity to AKT/mTOR inhibitors [46]. Secondly, B7-H3 suppresses T-cell-mediated antitumor immunity by inducing M2-type polarization of tumor-associated macrophages in hepatocellular carcinoma, thereby promoting tumor development through the STAT3 signaling pathway [54]. Thirdly, B7-H3 plays a role in tumor promotion by influencing cell proliferation, metastasis, invasion, and epithelial-to-mesenchymal transition (EMT). For instance, B7-H3 knockdown in esophageal carcinoma and breast cancer suppresses tumor cell proliferation [47, 48], while in pancreatic cancer and gastric cancer, it reduces tumor cell migration and transwell invasion in vitro [49]. Furthermore, B7-H3 promotes EMT in glioma and hepatoma cells through JAK2/STAT3/Slug pathway activation [26, 50]. Lastly, B7-H3 enhances chemoresistance, as shown in human pancreatic ductal adenocarcinoma cells where B7-H3 silencing increases sensitivity to gemcitabine. These mechanisms provide valuable insights into the diverse roles of B7-H3 in cancer development and progression, warranting further investigation to fully elucidate its functions and potential therapeutic implications [51].

However, the assessing standard of B7-H3 positivity is different in different studies. Boorjian [38], Xylinas [33] and Li [37] considered cases with B7-H3 cell staining ≥ 10% as positive, in addition Li [37]subdivided B7-H3 positivity, with 10–29% defined as low expression, 30–60% defined as moderate expression and > 60% defined as intense expression. However, these methods are based on staining area only, on which Mahmoud [36] and Xu [32, 34, 35] also considered staining intensity. In Xu’ s study [32, 34, 35], quantification was made as follows: <33% of cancer cells—1; ≥33 to 66% of cancer cells—2; >66% of cancer cells—3; absent/weak staining—1; moderately intense staining—2; strong staining—3. By multiplying the above two scores, a total score of ≤ 3 was defined as low expression of B7-H3, and a total score of > 3 was defined as high expression of B7-H3. And Mahmoud [36] use H-score, which is equal to 1×(% cells weak expression) + 2×(% cells with moderate expression) + 3×(% cells strong expression). The groupings are as follows: negative (H-score = 0); Low (H-score ≥ 1 and < 120); high (H-score ≥ 120). Further research is needed on which assessment criteria are better.

In recent years, immunotherapy has made rapid advancements in the treatment of various types of cancer. Progress in molecular biology and antibody engineering has facilitated the development of strategies for targeting B7-H3 using multiple effector mechanisms. Many of these approaches have been successfully tested in vitro and in mouse models, demonstrating encouraging safety profiles and anti-tumor activity [55‐58]. These results have paved the way for clinical trials focusing on B7-H3 targeting. In the context of bladder cancer, Ma et al. [59] demonstrated an increase in CD69 expression on activated T cells (ATC) when treated with an anti-CD3-B7-H3 bispecific antibody (B7-H3Bi-Ab). CD69 is considered an early activation marker for T cells. B7-H3Bi-Ab-ATC have the capability to eliminate B7-H3-positive bladder cancer cells through the CD3-B7-H3 bridge mechanism, exhibiting significant cytotoxic activity against human bladder cancer cells. These findings suggest that B7-H3Bi-Ab enhances the killing potential of ATC against bladder cancer cells, offering a promising novel approach for the treatment of bladder cancer.

Although efforts have been made, our study still has some limitations. Firstly, the main ethnic populations were European and Asian, and African representation was insufficient. Secondly, the pooled analyses of the relationships between B7-H3 expression and prognosis and patient clinicopathological features, such as tumor grade and T stage, were based on a relatively small number of studies. More research is needed to validate these results and obtain more reliable conclusions. Thirdly, the included studies used different criteria for judging the positive or negative expression of B7-H3, leading to some heterogeneity in the meta-analysis. This could affect the overall accuracy of the results. Fourthly, we did not include unpublished articles and conference abstracts in the meta-analysis due to insufficient information, which may introduce selection bias and potentially miss relevant data. Fifthly, the sample size of our meta-analysis was relatively small, which may limit the statistical power to detect certain associations, especially in the analysis of overall survival. Lastly, because some included articles did not report detailed survival data, we had to rely on the Kaplan-Meier curve for survival analysis, which might lead to potential overestimation or underestimation of actual survival data. To address these limitations, future research should focus on conducting well-designed clinical randomized controlled studies with larger sample sizes that encompass diverse racial backgrounds to provide more robust and comprehensive insights into the relationship between B7-H3 expression and bladder cancer.

In conclusion, our study confirms that B7-H3 is overexpressed in bladder cancer (BC), and its expression is closely related to tumor invasion and recurrence in BC. Furthermore, B7-H3 expression has shown no association with the survival of bladder cancer patients, suggesting that B7-H3 may play multiple roles in the pathophysiology of bladder cancer. To address the limitations of the current meta-analysis, it is imperative that future studies with larger sample sizes and standardized methodologies be conducted. Additionally, investigating the underlying mechanisms by which B7-H3 influences tumor progression holds the potential to contribute to the development of innovative treatment strategies for bladder cancer.