Jimena Tosello Boari, Wilfrid Richer, Yoann Missolo-Koussou, Elisa Bonnin, Sebastien Lemoine, Marco Antônio Pretti, Rodrigo Nalio Ramos, Jeremy Mesple, Jordan Denizeau, Sylvain Baulande, Mylène Bohec, Sonia Lameiras, Philippe Martin, Rafael Mena Osuna, Wenjie Sun, Marine Lefevre, Agathe Seguin-Givelet, Christine Sedlik, Filipa Ramos, Saumya Kumar, Leïla Perié, Luis Graça, Olivier Lantz, Edith Borcoman, Nicolas Girard, Joshua J Waterfall, Eliane Piaggio
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.