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. 2022 Aug:171:133-142.
doi: 10.1016/j.ejca.2022.05.022. Epub 2022 Jun 16.

B7-H4 correlates with clinical outcome and immunotherapeutic benefit in muscle-invasive bladder cancer

Zhaopei Liu  1 , Kaifeng Jin  2 , Han Zeng  3 , Fei Shao  4 , Yuan Chang  1 , Yiwei Wang  5 , Le Xu  6 , Zewei Wang  7 , Xingang Cui  8 , Yu Zhu  9 , Jiejie Xu  10
Affiliations

B7-H4 correlates with clinical outcome and immunotherapeutic benefit in muscle-invasive bladder cancer

Zhaopei Liu et al. Eur J Cancer. 2022 Aug.

Abstract

Aim: B7-H4, a sibling to PD-L1 in B7 family, has been reported to be a novel immune checkpoint that is prevalent among non-inflamed tumors. Herein, we attempt to explore the potential of B7-H4 in survival prediction and therapeutic guidance in muscle-invasive bladder cancer (MIBC) patients.

Methods: This study included 391 patients from The Cancer Genome Atlas (TCGA) database and 122 patients from Zhongshan (ZS) Hospital. The evaluation of response to PD-L1 inhibitors was based on 270 patients in IMvigor210 cohort. Kaplan-Meier survival and multivariate analyses were performed to assess clinical outcomes in three cohorts. The correlation of B7-H4 expression with immune contexture and genomic alterations was analyzed based on immunohistochemistry, Microenvironment Cell Populations-counter (MCP-counter) tool, and whole-exome sequencing.

Results: MIBC patients with the high level of B7-H4 expression (B7-H4high) were found to possess an inferior overall and recurrence-free survival. Nonetheless, substantial clinical benefits of cisplatin-based chemotherapy and anti-PD-L1 immunotherapy were observed in these patients. After identifying a positive correlation between B7-H4 and tumor mutation burden (TMB), clinical benefits in B7-H4high TMBhigh subgroup were found to be the most upon PD-L1 blockade. Further studies revealed that B7-H4high subgroup was featured by non-inflamed immune contexture and cell cycle-related gene alterations.

Conclusions: Despite adverse clinical outcomes, B7-H4high patients possessed superior responsiveness to chemotherapy and immunotherapy. B7-H4 stratification could also synergize with TMB to pinpoint the patients who benefited most from immunotherapy. The clinical exploration of B7-H4 as a companion predictor could allow clinicians to direct proper therapeutic agents to patients.

Keywords: Adjuvant chemotherapy; B7-H4; Immune checkpoint blockade; Muscle-invasive bladder cancer; Tumor mutation burden.

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Conflict of interest statement

Conflict of interest statement The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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