Discovery of an independent poor-prognosis subtype associated with tertiary lymphoid structures in breast cancer

Ruiqi Liu; Xiaoqian Huang; Shiwei Yang; Wenbo Du; Xiaozhou Chen; Huamei Li

doi:10.3389/fimmu.2024.1364506

Discovery of an independent poor-prognosis subtype associated with tertiary lymphoid structures in breast cancer

Front Immunol. 2024 Mar 20:15:1364506. doi: 10.3389/fimmu.2024.1364506. eCollection 2024.

Authors

Ruiqi Liu^#¹, Xiaoqian Huang^#¹, Shiwei Yang¹, Wenbo Du², Xiaozhou Chen¹, Huamei Li²

Affiliations

¹ School of Mathematics and Computer Science, Yunnan Minzu University, Kunming, China.
² Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, China.

^# Contributed equally.

Abstract

Introduction: Tertiary lymphoid structures (TLSs) are ectopic lymphoid formations that arise in non-lymphoid tissues due to chronic inflammation. The pivotal function of TLSs in regulating tumor invasion and metastasis has been established across several cancers, such as lung cancer, liver cancer, and melanoma, with a positive correlation between increased TLS presence and improved prognosis. Nevertheless, the current research about the clinical significance of TLSs in breast cancer remains limited.

Methods: In our investigation, we discovered TLS-critical genes that may impact the prognosis of breast cancer patients, and categorized breast cancer into three distinct subtypes based on critical gene expression profiles, each exhibiting substantial differences in prognosis (p = 0.0046, log-rank test), with Cluster 1 having the best prognosis, followed by Cluster 2, and Cluster 3 having the worst prognosis. We explored the impact of the heterogeneity of these subtypes on patient prognosis, the differences in the molecular mechanism, and their responses to drug therapy and immunotherapy. In addition, we designed a machine learning-based classification model, unveiling highly consistent prognostic distinctions in several externally independent cohorts.

Results: A notable marker gene CXCL13 was identified in Cluster 3, potentially pivotal in enhancing patient prognosis. At the single-cell resolution, we delved into the adverse prognosis of Cluster 3, observing an enhanced interaction between fibroblasts, myeloid cells, and basal cells, influencing patient prognosis. Furthermore, we identified several significantly upregulated genes (CD46, JAG1, IL6, and IL6R) that may positively correlate with cancer cells' survival and invasive capabilities in this subtype.

Discussion: Our study is a robust foundation for precision medicine and personalized therapy, presenting a novel perspective for the contemporary classification of breast cancer.

Keywords: breast cancer; prognosis; subtypes; tertiary lymphoid structures; tumor microenvironment.

Publication types

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

MeSH terms

Breast Neoplasms* / genetics
Breast Neoplasms* / pathology
Female
Humans
Liver Neoplasms*
Lung Neoplasms* / pathology
Prognosis
Tertiary Lymphoid Structures* / pathology

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the Jiangsu Funding Program for Excellent Postdoctoral Talent (2022ZB699 to HL).