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

Zhaopei Liu; Kaifeng Jin; Han Zeng; Fei Shao; Yuan Chang; Yiwei Wang; Le Xu; Zewei Wang; Xingang Cui; Yu Zhu; Jiejie Xu

doi:10.1016/j.ejca.2022.05.022

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

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

Authors

Zhaopei Liu¹, Kaifeng Jin², Han Zeng³, Fei Shao⁴, Yuan Chang¹, Yiwei Wang⁵, Le Xu⁶, Zewei Wang⁷, Xingang Cui⁸, Yu Zhu⁹, Jiejie Xu¹⁰

Affiliations

¹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China.
² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
³ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁵ Department of Urology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁶ Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁷ Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: zwwang12@fudan.edu.cn.
⁸ Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: cuixingang@xinhuamed.com.cn.
⁹ Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China. Electronic address: yuzhu10@fudan.edu.cn.
¹⁰ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. Electronic address: jjxufdu@fudan.edu.cn.

PMID: 35717821
DOI: 10.1016/j.ejca.2022.05.022

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-H4^high) 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-H4^high TMB^high subgroup were found to be the most upon PD-L1 blockade. Further studies revealed that B7-H4^high subgroup was featured by non-inflamed immune contexture and cell cycle-related gene alterations.

Conclusions: Despite adverse clinical outcomes, B7-H4^high 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen
Biomarkers, Tumor / genetics
Humans
Immunohistochemistry
Immunotherapy
Muscles / chemistry
Tumor Microenvironment
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / genetics
V-Set Domain-Containing T-Cell Activation Inhibitor 1 / metabolism*

Substances

B7-H1 Antigen
Biomarkers, Tumor
V-Set Domain-Containing T-Cell Activation Inhibitor 1
VTCN1 protein, human