Regulatory B cells promote the immunosuppressive microenvironment and progression of clear cell renal cell carcinoma

Qintao Ge; Siqi Zhou; Jiahe Lu; Shiqi Ye; Aihetaimujiang Anwaier; Xi Tian; Yonghao Chen; Hailiang Zhang; Dingwei Ye; Wenhao Xu

doi:10.1093/immadv/ltaf013

Regulatory B cells promote the immunosuppressive microenvironment and progression of clear cell renal cell carcinoma

Immunother Adv. 2025 May 15;5(1):ltaf013. doi: 10.1093/immadv/ltaf013. eCollection 2025.

Authors

Qintao Ge^{1

2

3

4}, Siqi Zhou^{1

2

3}, Jiahe Lu^{1

2

3}, Shiqi Ye^{1

2

3}, Aihetaimujiang Anwaier^{1

2

3}, Xi Tian^{1

2

3}, Yonghao Chen⁵, Hailiang Zhang^{1

2

3}, Dingwei Ye^{1

2

3}, Wenhao Xu^{1

2

3}

Affiliations

¹ Department of Urology, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, 200032 PR China.
² Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, P.R. China.
³ Shanghai Genitourinary Cancer Institute, Shanghai, PR China.
⁴ Qingdao Institute, School of Life Medicine, Fudan University, Qingdao, PR China.
⁵ West China Medical Center of Sichuan University, Chengdu, PR China.

Abstract

Background: Regulatory B cells (Bregs) are critical mediators of immune modulation and tumor progression. However, their prognostic relevance and mechanistic roles in clear cell renal cell carcinoma (ccRCC) remain insufficiently explored.

Methods: A comprehensive pancancer strategy was implemented to assess the prognostic role of Breg cells. Spatial transcriptomics, multiplex immunofluorescence (mIF), and immunohistochemistry were performed to investigate Breg localization and immunosuppressive functionality in ccRCC. A machine learning-derived Breg signature (CMLBregS) was established and validated for risk stratification and immune profiling.

Results: Elevated Breg signatures were prominently observed in ccRCC and were associated with advanced T stage, higher tumor grades, and decreased progression-free survival. Spatial transcriptomics and mIF revealed that CD20⁺CD23⁺IL10V Breg cells exert immunosuppressive effects, with or without of the presence of tertiary lymphoid structures. The CMLBregS, comprising 16 Breg-related genes, effectively stratified built a binary classification system. A high-CMLBregS score was linked to an immunosuppressive TME characterized by upregulated IL-10 and TGF-β production, suppression of lymphocyte activation, reduced T cell proliferation, and dampened innate immune responses. Patients with higher CMLBregS scores demonstrated significantly worse clinical outcomes across multiple cohorts. Among CMLBregS-related genes, IRF4 emerged as a key prognostic marker, strongly correlating with IL-10 and PDCD1 expression. Notably, patients with elevated CMLBregS scores exhibited poorer responses to immune checkpoint blockade therapy and more aggressive disease progression during immunotherapy.

Conclusion: This study underscores the pivotal role of Bregs in promoting immune suppression and poor prognosis in ccRCC. The CMLBregS model offers a robust prognostic tool, identifies patients less likely to benefit from immunotherapy, and highlights IRF4 as a potential alternative target. These findings provide a foundation for future strategies aimed at overcoming Breg-mediated immunosuppression in ccRCC.

Keywords: clear cell renal cell carcinoma (ccRCC); immune checkpoint blockade (ICB); immunosuppression; regulatory B cells (Bregs); tumor microenvironment (TME).