Title | Tumor-specific draining lymph node CD8 T cells orchestrate an anti-tumor response to neoadjuvant PD-1 immune checkpoint blockade. |
Publication Type | Journal Article |
Year of Publication | 2025 |
Authors | Honigsberg R, Cruz T, Yoffe L, Tang MStephanie, Dicle O, Markowitz G, Michael M, Singh A, Altorki NK, Elemento O, Villena-Vargas J |
Journal | bioRxiv |
Date Published | 2025 Jun 01 |
ISSN | 2692-8205 |
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. |
DOI | 10.1101/2025.04.27.650862 |
Alternate Journal | bioRxiv |
PubMed ID | 40501950 |
PubMed Central ID | PMC12154853 |
Grant List | UH3 CA244697 / CA / NCI NIH HHS / United States |