Tertiary Lymphoid Structures are Linked to Enhanced Antitumor Immunity and Better Prognosis in Muscle-Invasive Bladder Cancer

Sep 21, 2026

Muscle-invasive bladder cancer (MIBC) has a poor prognosis and lacks reliable biomarkers. Tertiary lymphoid structures (TLS), known to correlate with better outcomes in some malignancies, are assessed for their role in MIBC using multi-omics profiling. Single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and immunohistochemistry reveal that higher B-cell and TLS abundance associates with improved prognosis and stronger antitumor immunity. Mechanistically, CXCL13 from clonally expanded CXCL13+ T cells drives TLS formation via CXCR5 on NR4A2+ B cells, while TLS-resident plasma cells produce IGHG that may enhance C1QC+ macrophage phagocytosis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

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Introduction

Background and clinical need for biomarkers

TLS in cancer immunotherapy and prognosis

Unclear mechanisms of TLS in MIBC

RESEARCH ARTICLE [www.advancedscience.com](www.advancedscience.com) Tertiary Lymphoid Structures are Linked to Enhanced Antitumor Immunity and Better Prognosis in Muscle-Invasive Bladder Cancer Jiaxing Lin, Shan Jiang, Baoqiang Chen, Yiqing Du, Caipeng Qin, Yuxuan Song, Yun Peng, Mengting Ding, Jilin Wu, Yihan Lin,* and Tao Xu* The prognosis for muscle-invasive bladder cancer (MIBC) remains poor, and reliable prognostic markers have yet to be identiﬁed. Tertiary lymphoid structures (TLS) have been associated with favorable outcomes in certain cancers. However, the relationship between TLS and MIBC remains unclear. A multi-omics approach is utilized, leveraging single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and immunohistochemistry, to investigate the roles of B cells and TLS in MIBC. These ﬁndings indicate that elevated levels of B cells and TLS correlate with improved prognoses inpatients with MIBC, aligning with the robust antitumor immune responses observed in the TLS region. From a mechanistic perspective, CXCL13 serves as a critical cytokine for TLS formation in MIBC, primarily secreted by clonally expanded CXCL13+ T cells. This cytokine interacts with the CXCR5 receptor on NR4A2+ B cells, promoting TLS development. Plasma cells arising within the TLS microenvironment predominantly produce the IGHG antibody, potentially enhancing the phagocytic capabilities ofC1QC+ macrophages. From an application standpoint, a TLS-speciﬁc gene signature is developed that eﬀectively predicts outcomes in MIBC and other cancers. This study highlights the prognostic potential of TLS in MIBC and reveals immune mechanisms, oﬀering insights for personalized treatment strategies. limited treatment options. [1] The primary treatments for MIBC currently include cisplatin-based neoadjuvant chemotherapy and radical cystectomy, yet the overall 5-year survival rate remains only 60–70% . [2] Recently, immune checkpoint inhibitors (ICB), such as anti-PD-1/PD-L1 antibodies, have demonstrated signiﬁcant eﬃcacy in treating MIBC, particularly in patients with advanced disease. However, only a subset of patients exhibited a durable response to immunotherapy, underscoring the critical need for new biomarkers to more accurately predict therapeutic response. The presence of tertiary lymphoid structures (TLS) has been associated with improved clinical outcomes and enhanced responses to immunotherapy in several cancers. [3–5] TLS are organized aggregates of immune cells that form in non-lymphoid tissues,[6] with B cells being the predominant cell type. Some studies have examined the prognostic signiﬁcance of TLS in UC cohorts. Research suggests that the clustering of highly expressed TLSrelated genes is associated with a better 1. Introduction Urothelial carcinoma (UC) is a prevalent and lethal malignancy of the urinary system. Muscle-invasive bladder cancer (MIBC), a clinical subtype of UC, is associated with a poor prognosis and prognosis. [7] In one cohort of UC patients treated with combined CTLA-4 and PD-1 inhibitors, responders exhibited higher baseline TLS density.[8] However, in another cohort receiving similar treatment, baseline TLS did not signiﬁcantly aﬀect prognosis, likely due to corticosteroid use, which may have inhibited J. Lin, S. Jiang, Y. Du, C. Qin, Y. Song, Y. Peng, M. Ding, J. Wu, T. Xu Department of Urology Peking University People’s Hospital Beijing 100044, China E-mail: [xutao@pkuph.edu.cn](xutao@pkuph.edu.cn) The ORCID identiﬁcation number(s) for the author(s) of this article can be found under [https://doi.org/10.1002/advs.202410998](https://doi.org/10.1002/advs.202410998)[ ](https://doi.org/10.1002/advs.202410998)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

FAQs

Why is prognosis prediction important in muscle-invasive bladder cancer (MIBC)?

The document states that MIBC has a poor prognosis and that reliable prognostic markers have not yet been identified, making prediction and biomarker development a critical need.

What evidence links tertiary lymphoid structures (TLS) to MIBC outcomes?

Using a multi-omics approach, the study finds that elevated B cells and TLS levels correlate with improved prognoses in MIBC patients, consistent with robust antitumor immune responses in the TLS region.

How does the study explain TLS formation and function in MIBC?

It identifies CXCL13 as a key cytokine for TLS formation, mainly secreted by clonally expanded CXCL13+ T cells. CXCL13 interacts with CXCR5 on NR4A2+ B cells to promote TLS development, and plasma cells within TLS produce IGHG that may enhance C1QC+ macrophage phagocytosis.

Sep 21, 2026

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