{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T13:49:40Z","timestamp":1776001780824,"version":"3.50.1"},"posted":{"date-parts":[[2025,4,30]]},"group-title":"Cancer Biology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T00:00:00Z","timestamp":1745971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Elucidating the anti-tumor role of tumor-draining lymph nodes (tdLNs) in patients could offer critical mechanistic insight and shift therapeutic strategies from a tumor-centric approach to one that considers tumor-immune system interplay. Our study characterizes benign tdLNs T cell anti-tumor responses beyond initial T cell priming in patients with resectable non-small cell lung cancer. We further investigated whether tumor-specific tdLN T cells were altered by immune checkpoint blockade (ICB) locally and systemically. We performed single-cell TCR lineage tracing and transcriptomic profiling on 672,886 CD8 T cells from 41 tumor, benign tdLN, and blood samples in 14 patients treated with or without neoadjuvant chemoimmunotherapy (ChemoIO). Using deep-integrating clonal tracking with machine learning-based transcriptional analysis, our findings revealed that benign tdLNs locally and independently orchestrate two transcriptionally distinct tumor-specific memory CD8 T cell populations: one with ZNF683+ CXCR6+ tumor tissue-residency potential, and another with cytotoxic memory potential. Furthermore, tdLN-derived clones not only constitute the dominant tumor-infiltrating (75%) and circulating (&gt;90%) tumor-specific expanded T cell populations but also preserve their transcriptionally distinct subset identities within the tumor T cell effector state. ChemoIO selectively increased the clonal diversity and cytotoxic memory\/TEMRA programs of tdLN-derived clones locally and systemically, both of which remained unchanged in clones lacking tdLN TCR lineage. In conclusion, the tdLN locally orchestrates tumor-reactive and ChemoIO-reactive transcriptional distinct T cell subsets that shape the circulating blood and tumor T cell environments. These findings represent a clinical paradigm shift with implications regarding the extent of tdLN resection during surgery, timing of ChemoIO treatment, and the development of memory T cell-based immunotherapies.<\/jats:p>","DOI":"10.1101\/2025.04.27.650862","type":"posted-content","created":{"date-parts":[[2025,4,30]],"date-time":"2025-04-30T23:27:49Z","timestamp":1746055669000},"source":"Crossref","is-referenced-by-count":5,"title":["Tumor-specific draining lymph node CD8 T cells orchestrate an anti-tumor response to neoadjuvant PD-1 immune checkpoint blockade"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5489-4693","authenticated-orcid":false,"given":"Rachel","family":"Honigsberg","sequence":"first","affiliation":[{"name":"Meining School of Biomedical Engineering, Cornell University, Ithaca, NY, USA"},{"name":"Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY, USA"},{"name":"Englander Institute for Precision Medicine, Weill Cornell 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