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A lymph node-tumor spatiotemporal atlas of exhausted T cell clone evolution

ABSTRACT: Current surgical guidelines overlook preserving uninvolved lymph nodes (uiLNs) in non-small cell lung cancer, principally stemming from an underappreciation of their critical role in anti-tumor immunity. Here, we discovered a significant immunosuppressive microenvironment in metastatic lymph nodes. In contrast, CD200+ progenitor exhausted T cells (Tpex) markedly expanded within uiLNs following immunotherapy. Effective clonal sharing of exhausted T cells between uiLNs and tumors correlated strongly with complete pathological response. Previously unrecognized tumor-resident C1QA+ dendritic cells secreted CXCL9, facilitating T cell recruitment, whereas fibroblast-enriched neighborhoods in non-responders created immunosuppressive barriers hindering CXCL9 diffusion and CD200+ Tpex migration. Finally, we confirmed that tumor-reactive Tex clones from uiLNs could persist systemically and identified two neoantigen peptides as direct targets of these tumor-reactive Tex cells. Our study unprecedentedly elucidates the spatiotemporal dynamics of immunotherapy-responsive T cell subsets in LN-tumor axis and provides compelling evidence to support selective LN dissection strategies to preserve uiLNs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE318850 | GEO | 2026/02/13

REPOSITORIES: GEO

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