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.