Tumor-distal mediastinal lymph nodes harbor tumor-related progenitor exhausted T cells in lung cancer after neoadjuvant chemoimmunotherapy.
basic_science · Level V
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- Also identified by DOI 10.1016/j.xcrm.2026.102964.
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Abstract
Tumor-proximal mediastinal lymph nodes (tpMLNs) support progenitor exhausted CD8<sup>+</sup> T cells (CD8<sup>+</sup> Tpex)-mediated antitumor immunity, but the role of tumor-distal mediastinal lymph nodes (tdMLNs) in lung squamous cell carcinoma (LUSC) after neoadjuvant chemoimmunotherapy remains unclear. Single-cell immunophenotypic analysis of 28 samples from five anatomic sites in five LUSC patients receiving neoadjuvant chemoimmunotherapy reveals similar immune cell compositions between tpMLNs and tdMLNs. Notably, terminally differentiated exhausted CD8<sup>+</sup> T lymphocytes (CD8<sup>+</sup> Tex-term) in tumors share clonal lineages with CD8<sup>+</sup> Tpex populations in both tpMLNs and tdMLNs. Multiplex immunofluorescence analysis confirms TOX<sup>+</sup>TCF-1<sup>+</sup>CXCL13<sup>+</sup> CD8<sup>+</sup> Tpex in both tpMLNs and tdMLNs, but not in primary tumors. Clonal tracking at 1, 6, and 18 months post-surgery detects both tumor-derived CD8<sup>+</sup> Tex-term and CD8<sup>+</sup> Tpex-related clones in peripheral blood. These findings suggest that tdMLNs perform immunological functions like tpMLNs in LUSC antitumor immune responses. Therefore, we propose preserving tdMLNs during surgical resection to maintain these immune effector cell reserves and support postoperative immunological competence and adjuvant therapeutic outcomes.