{"doi":"10.1101/2025.04.27.650862","title":"Tumor-specific draining lymph node CD8 T cells orchestrate an anti-tumor response to neoadjuvant PD-1 immune checkpoint blockade","abstract":"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 (>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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555521,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":1,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1454301,"name":"Tatiana Cruz","orcid":null,"position":1,"is_corresponding":false},{"id":375904,"name":"Liron Yoffe","orcid":"0000-0002-3040-8205","position":2,"is_corresponding":false},{"id":1454302,"name":"Meixian Stephanie Tang","orcid":null,"position":3,"is_corresponding":false},{"id":1454303,"name":"Ozge Dicle","orcid":null,"position":4,"is_corresponding":false},{"id":276041,"name":"Geoffrey J. Markowitz","orcid":"0000-0003-3915-8078","position":5,"is_corresponding":false},{"id":1453812,"name":"Marissa Michael","orcid":"0000-0002-0313-3947","position":6,"is_corresponding":false},{"id":861830,"name":"Arshdeep Singh","orcid":"0000-0001-7163-0454","position":7,"is_corresponding":false},{"id":770323,"name":"Nasser K. Altorki","orcid":"0000-0001-9754-9945","position":8,"is_corresponding":false},{"id":41043,"name":"Olivier Elemento","orcid":"0000-0002-8061-9617","position":9,"is_corresponding":false},{"id":666437,"name":"Jonathan Villena‐Vargas","orcid":"0000-0002-8248-666X","position":10,"is_corresponding":false},{"id":1453811,"name":"Rachel Honigsberg","orcid":"0000-0001-5489-4693","position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:59.329539Z","pmid":"40501950","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}