{"doi":"10.1101/2024.12.31.630523","title":"Acquisition of discrete immune suppressive barriers contributes to the initiation and progression of preinvasive to invasive human lung cancer","abstract":"Computerized chest tomography (CT)-guided screening in populations at risk for lung cancer has increased the detection of preinvasive subsolid nodules, which progress to solid invasive adenocarcinoma. Despite the clinical significance, there is a lack of effective therapies for intercepting the progression of preinvasive to invasive adenocarcinoma. To uncover determinants of early disease emergence and progression, we used integrated single-cell approaches, including scRNA-seq, multiplexed imaging mass cytometry and spatial transcriptomics, to construct the first high-resolution map of the composition, lineage/functional states, developmental trajectories and multicellular crosstalk networks from microdissected non-solid (preinvasive) and solid compartments (invasive) of individual part-solid nodules. We found that early disease initiation and subsequent progression are associated with the evolution of immune-suppressive cellular phenotypes characterized by decreased cytotoxic CD8 T and NK cells, increased T cell exhaustion and accumulation of immunosuppressive regulatory T cells (Tregs) and M2-like macrophages expressing TREM2. Within Tregs, we identified a unique population of 4-1BB+ Treg subset enriched for the IL2-STAT5 suppressive pathway with transcription profiles supporting discrete metabolic alterations. Spatial analysis showed increased density of suppressive immune cells around tumor cells, increased exhaustion phenotype of both CD4 and CD8 T cells expressing chemokine CXCL13, and spatial microcomplex of endothelial and lymphocyte interactions within tertiary lymphoid structures. The single-cell architecture identifies determinants of early disease emergence and progression, which may be developed not only as diagnostic/prognostic biomarkers but also as targets for disease interception. Additionally, our dataset constitutes a valuable resource for the preinvasive lung cancer research community.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":555824,"datarank":0.17836644508813482,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.013574601787918361,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.013574601787918361,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9525,"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":423905,"name":"Bhavneet Bhinder","orcid":"0000-0001-6685-8761","position":1,"is_corresponding":false},{"id":775338,"name":"Sung Wook Kang","orcid":"0000-0002-0504-928X","position":2,"is_corresponding":false},{"id":1454702,"name":"Haoran Zhang","orcid":"0000-0002-6883-1375","position":3,"is_corresponding":false},{"id":861830,"name":"Arshdeep Singh","orcid":"0000-0001-7163-0454","position":4,"is_corresponding":false},{"id":28988,"name":"Hiranmayi Ravichandran","orcid":"0000-0001-8671-7667","position":5,"is_corresponding":false},{"id":276041,"name":"Geoffrey J. 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McGraw","orcid":"0000-0001-9748-263X","position":13,"is_corresponding":false},{"id":105525,"name":"Alain Borczuk","orcid":"0000-0001-6807-8064","position":14,"is_corresponding":false},{"id":700627,"name":"Hyun‐Sung Lee","orcid":"0000-0001-8259-046X","position":15,"is_corresponding":false},{"id":770323,"name":"Nasser K. 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