{"doi":"10.1101/2025.05.05.651897","title":"Disrupted priming within draining lymph nodes drives immune quiescence in gastric cancer","abstract":"Abstract The gastric mucosa is characterized by continuous innate immune surveillance and inflammatory signaling, yet a high proportion of gastric carcinomas (GCs) are recalcitrant to immune-directed therapies. The mechanisms by which GCs evade adaptive immune surveillance within the highly antigenic microenvironment of the gastric mucosa remains unknown. To address this, we collected patient-matched tumor tissue, distant normal tissue, metastasis, and draining lymph nodes to generate a large-scale single-cell immune profiling dataset from 64 patients (n=179 samples, >150,000 cells). From single cell analysis, we identified two distinct sources of impaired tumor surveillance within tumor draining lymph nodes. First, we observed that a significant fraction of tumor draining lymph nodes had undergone cytokine-driven reprogramming, leading to reduced dendritic cell homing and limited T cell priming. Second, T cells undergoing successful activation exhibited limited expansion and constrained differentiation, marked by expression of the quiescence-associated transcription factor Kruppel-like Factor 2 ( KLF2 ). Overexpression of KLF2 in primary T cells limited both their differentiation and cytotoxic capacity. These findings implicate both impaired T cell priming and KLF2 -dependent T cell quiescence in limiting T cell immunity in gastric adenocarcinoma. We suggest these findings represent an emerging model for immune silencing in tumors developing from tissues with chronic inflammation.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":565370,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9452,"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":776913,"name":"Emily E. Stroobant","orcid":"0000-0002-6321-1695","position":1,"is_corresponding":false},{"id":422078,"name":"Hannah Lees","orcid":"0000-0002-1684-3075","position":2,"is_corresponding":false},{"id":867373,"name":"Ya-Hui Lin","orcid":"0000-0001-9874-0012","position":3,"is_corresponding":false},{"id":1180312,"name":"Shoji Shimada","orcid":null,"position":4,"is_corresponding":false},{"id":1082667,"name":"Miseker Abate","orcid":"0000-0001-5060-1208","position":5,"is_corresponding":false},{"id":1326037,"name":"Matthew Zatzman","orcid":"0000-0001-5235-4116","position":6,"is_corresponding":false},{"id":288782,"name":"Nicholas Ceglia","orcid":"0000-0001-9387-103X","position":7,"is_corresponding":false},{"id":3749,"name":"Samuel S. Freeman","orcid":"0000-0001-8285-0057","position":8,"is_corresponding":false},{"id":474712,"name":"Monika Laszkowska","orcid":"0000-0001-6816-3293","position":9,"is_corresponding":false},{"id":231581,"name":"Steven B. Maron","orcid":"0000-0002-8794-130X","position":10,"is_corresponding":false},{"id":22233,"name":"Andrew McPherson","orcid":"0000-0002-5654-5101","position":11,"is_corresponding":false},{"id":801953,"name":"Nicole Rusk","orcid":"0000-0003-2663-6288","position":12,"is_corresponding":false},{"id":811870,"name":"Eliyahu Havasov","orcid":null,"position":13,"is_corresponding":false},{"id":645607,"name":"Harrison Drebin","orcid":null,"position":14,"is_corresponding":false},{"id":820745,"name":"Ping Gu","orcid":"0000-0001-7681-1043","position":15,"is_corresponding":false},{"id":250490,"name":"Laura H. Tang","orcid":"0000-0001-5735-9354","position":16,"is_corresponding":false},{"id":90740,"name":"Yelena Y. Janjigian","orcid":"0000-0002-5357-5858","position":17,"is_corresponding":false},{"id":74618,"name":"Ruslan Soldatov","orcid":"0000-0002-5670-5881","position":18,"is_corresponding":false},{"id":1159879,"name":"Ronan Chaligné","orcid":"0000-0001-5788-5848","position":19,"is_corresponding":false},{"id":22198,"name":"Sohrab P. Shah","orcid":"0000-0001-6402-523X","position":20,"is_corresponding":false},{"id":533606,"name":"Vivian E. Strong","orcid":"0000-0001-5044-1662","position":21,"is_corresponding":false},{"id":78951,"name":"Santosha A. 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