Clonal sharing and plasticity of follicular CD4 + T cells across lymph nodes and tumors in non-small cell lung cancer
Tumor-invaded lymph nodes (LNs) are critical but poorly studied hubs of anti-tumor immunity. Using single-cell transcriptome, clonotype, and chromatin profiling, we analyze CD4 + T cells from blood, LNs, and tumors of NSCLC patients. LNs and tumors are enriched in follicular regulatory T cells (Treg-Tfr), follicular-like conventional T cells (Tconv-Tfh and Tconv-CXCL13), and tissue-resident Tregs (Treg-Trm). These populations are predicted to share a transcriptional program of activation and tissue adaptation, driven by BATF. Additionally, these subsets show extensive LN-tumor clonal sharing, indicating recirculation, and are enriched in transcriptional signatures of tumor reactivity. Treg-Tfr cells function as progenitors bifurcating into Treg-Trm or ex-Tregs with a Tfh-like CXCL13+ effector phenotype. Follicular subsets in LNs and tumors are transcriptionally and epigenetically similar and localize in germinal-center-like niches. Overall, tumor-invaded LNs and tumors coordinate the generation and maintenance of tumor-reactive CD4+ lineages, identifying highly plastic follicular T cells as therapeutic checkpoints to reinforce anti-tumor responses. To provide additional insights into the biology of CD4 + T cells in cancer, here the authors report a multi-omics analysis of CD4 + T cells from matched blood, tumor invaded lymph nodes (LNs), and tumor tissues of patients with non-small cell lung cancer, showing that tumor-invaded LNs and tumors harbor clonally linked and plastic follicular CD4+T cell subsets.
Authors
- Eliane Piaggio (ORCID: https://orcid.org/0000-0002-2455-8442)
- Joshua J. Waterfall (ORCID: https://orcid.org/0000-0002-3762-5050)
- Mylène Bohec (ORCID: https://orcid.org/0000-0002-6530-596X)
- Marine Lefèvre (ORCID: https://orcid.org/0000-0003-2216-1481)
- Rodrigo Nalio Ramos (ORCID: https://orcid.org/0000-0003-1249-4733)
- Jérémy Mesple (ORCID: https://orcid.org/0000-0003-2537-3463)
- Elisa Bonnin (ORCID: https://orcid.org/0009-0005-6544-2736)
- Wilfrid Richer (ORCID: https://orcid.org/0000-0003-1802-3529)
- Agathe Seguin‐Givelet (ORCID: https://orcid.org/0000-0002-2906-4433)
- Leïla Perié (ORCID: https://orcid.org/0000-0003-0798-4498)
- Sonia Lameiras
- Christine Sedlik (ORCID: https://orcid.org/0000-0001-8502-0905)
- Olivier Lantz (ORCID: https://orcid.org/0000-0003-3161-7719)
- Sébastien Lemoine
- Wenjie Sun (ORCID: https://orcid.org/0000-0002-3100-2346)
- Yoann Missolo-Koussou (ORCID: https://orcid.org/0000-0002-3815-3980)
- Sylvain Baulande (ORCID: https://orcid.org/0000-0003-3104-1684)
- Luís Graça (ORCID: https://orcid.org/0000-0001-6935-8500)
- Édith Borcoman (ORCID: https://orcid.org/0000-0002-5393-5657)
- Jordan Denizeau
- Rafael Mena Osuna
- Jimena Tosello Boari
- Marco Antônio Pretti
- Saumya Kumar
- Philippe Martin
- Filipa Ramos
- Nicolas Girard
Institutions
- Centre National de la Recherche Scientifique (FR)
- University of Lisbon (PT)
- Inserm (FR)
- Université de Versailles Saint-Quentin-en-Yvelines (FR)
- Université Paris Sciences et Lettres (FR)
- Université Paris-Saclay (FR)
- Sorbonne Université (FR)
- Institute Mutualiste Montsouris (FR)
- Institut du Thorax (FR)
- Physique des Cellules et Cancers (FR)
- Instituto Gulbenkian de Ciência (PT)
- Institut Curie (FR)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-08-20
- DOI
- https://doi.org/10.1038/s41467-026-76101-6
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Equipex
- European Commission
- Agence Nationale de la Recherche
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Direction Générale de l’offre de Soins
- HORIZON EUROPE Framework Programme