ArticleThe Journal of clinical investigation2021
Functional Th1-oriented T follicular helper cells that infiltrate human breast cancer promote effective adaptive immunity.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 114 papers, 2 of them syntheses that pooled it.
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Who cites it
114 citing papers in PubMed, 2 syntheses or guidelines pooled it, 149 citations in OpenAlex.
- The soldiers needed to be awakened: Tumor-infiltrating immune cells.Frontiers in genetics · 2022Pooled it
- The Presence of Tertiary Lymphoid Structures Provides New Insight Into the Clinicopathological Features and Prognosis of Patients With Breast Cancer.Frontiers in immunology · 2022Pooled it
- Neoadjuvant tislelizumab (anti-PD-1 antibody) plus chemotherapy in patients with advanced epithelial ovarian cancer: the exploratory NAIVE trial.Signal transduction and targeted therapy · 2026Trial
- Phase II Clinical Trial of Pembrolizumab and Chemotherapy Reveals Distinct Transcriptomic Profiles by Radiologic Response in Metastatic Triple-Negative Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Trial
- Modulation of the response to immunotherapy in triple-negative breast cancer: the role of the microbiota and microbial metabolites in the tumor microenvironment.Gut microbes · 2026Review
- Review
- Regulation of follicular helper T cell subset differentiation in health and disease.Journal of molecular medicine (Berlin, Germany) · 2026Review
- Tertiary lymphoid structures in cancer: their development, composition, clinical prognosis, and the drivers of the anti-tumor responses.Molecular biomedicine · 2026Review
- Migration of immune cells in tumors and inflammation: molecular mechanisms and therapeutic targets.Signal transduction and targeted therapy · 2026Review
- The Ki-67 proliferation index in tertiary lymphoid structures as a predictor of survival outcomes in patients with resectable non-small cell lung cancer.BMC cancer · 2026Article
- Therapeutic potential of tertiary lymphoid structures in breast cancer (Review).Molecular medicine reports · 2026Review
- The formation and function of tertiary lymphoid structures.Biomarker research · 2026Review
- Anti-VEGF vascular remodeling drives germinal center B cell-rich tertiary lymphoid structures during antibody-toxin and anti-CD40 combination therapy in glioblastoma.Research square · 2026Article
- ADAM9 in tumor biology: molecular functions, clinical implications, and therapeutic targeting.Cellular & molecular biology letters · 2026Review
- The MEK1/2-IRF4 axis fosters T follicular helper cell differentiationand antitumor humoral immune response.Journal of translational medicine · 2026Article
- Stability and progressive differentiation of TNature immunology · 2026Article
- Proteotranscriptomic Dissection of Breast Cancer T Cell States Identifies CD103+ Tfh-derived Cytotoxic Cells Linked to Immunotherapy Response.Research square · 2026Article
- Mechanisms of T cell-mediated antitumor immunity within tertiary lymphoid structures.Frontiers in immunology · 2026Review
- Guardians of immunity: the role of tumour-draining lymph node in cancer immunity.Frontiers in cell and developmental biology · 2026Review
- The immune microenvironment of HPV-associated cancers: from viral oncogenesis to immunotherapy response.Frontiers in immunology · 2026Review
54 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 5 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
We previously demonstrated that tumor-infiltrating lymphocytes (TIL) in human breast cancer sometimes form organized tertiary lymphoid structures (TLS) characterized by CXCL13-producing T follicular helper (Tfh) cells. The present study found that CD4+ Tfh TIL, CD8+ TIL, and TIL-B, colocalizing in TLS, all express the CXCL13 receptor CXCR5. An ex vivo functional assay determined that only activated, functional Th1-oriented Tfh TIL (PD-1hiICOSint phenotype) provide help for immunoglobulin and IFN-γ production. A functional Tfh TIL presence signals an active TLS, characterized by humoral (immunoglobulins, Ki-67+ TIL-B in active germinal centers) and cytotoxic (GZMB+CD8+ and GZMB+CD68+ TIL plus Th1 gene expression) immune responses. Analysis of active versus inactive TLS in untreated patients revealed that the former are associated with positive clinical outcomes. TLS also contain functional T follicular regulatory (Tfr) TIL, which are characterized by a CD25+CXCR5+GARP+FOXP3+ phenotype and a demethylated FOXP3 gene. Functional Tfr inhibited functional Tfh activities via a glycoprotein A repetitions predominant (GARP)-associated TGF-β-dependent mechanism. The activity of tumor-associated TLS was dictated by the relative balance between functional Tfh TIL and functional Tfr TIL. These data provide mechanistic insight into TLS processes orchestrated by functional Th1-oriented Tfh TIL, including TIL-B and CD8+ TIL activation and immunological memory generation. Tfh TIL, regulated by functional Tfr TIL, are an expected key target of PD-1/PD-L1 blockade.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.