{"doi":"10.1101/2022.02.22.481404","title":"Systematic Elucidation and Pharmacological Targeting of Tumor-Infiltrating Regulatory T Cell Master Regulators","abstract":"Abstract Due to their immunosuppressive role, tumor-infiltrating regulatory T cells (TI-Tregs) represent attractive therapeutic targets. Analysis of TI vs. peripheral Tregs (P-Tregs) from 36 patients, across four malignancies, identified 17 candidate Master Regulators (MRs), predicted to mechanistically regulate TI-Tregs transcriptional state. In vivo , pooled CRISPR-KO screening, using a hematopoietic stem cell transplant model, confirmed essentiality of 7 of 17 MRs in TI-Treg recruitment and/or retention to the TME, without affecting other T cell subtypes, while individual knockout of the most significant MR (TRPS1) significantly reduced tumor allograft growth. TI-Treg drug perturbation profile analysis identified drugs capable of inverting the TI-Treg-specific MR activity signature at low concentration. Low dose treatment with gemcitabine (top prediction) inhibited tumor growth in immunocompetent but not immunocompromised allografts, increased PD-1 inhibitor efficacy, and depleted TI-Tregs in vivo . The study provides key insight into Treg infiltration mechanism and a gene reporter assay to identify additional small molecule inhibitors. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":298165,"datarank":0.29188652235829704,"base_score":1.9459101490553132,"endowment":1.9459101490553132,"self_citation_contribution":0.29188652235829704,"citation_network_contribution":0.0,"self_endowment_contribution":0.29188652235829704,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9551,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":266897,"name":"Casey R. Ager","orcid":"0000-0003-0507-700X","position":1,"is_corresponding":false},{"id":806459,"name":"Mikko Turunen","orcid":"0000-0001-5134-1559","position":2,"is_corresponding":false},{"id":263701,"name":"Thomas R. Nirschl","orcid":"0000-0002-3329-6229","position":3,"is_corresponding":false},{"id":369806,"name":"Mohsen Khosravi‐Maharlooei","orcid":"0000-0002-1394-9245","position":4,"is_corresponding":false},{"id":664765,"name":"Christopher M. Jackson","orcid":"0000-0002-5958-2004","position":5,"is_corresponding":false},{"id":987194,"name":"Vassan Yegnasubramanian","orcid":null,"position":6,"is_corresponding":false},{"id":79757,"name":"Angelo M. De Marzo","orcid":"0000-0003-4847-5307","position":7,"is_corresponding":false},{"id":265377,"name":"Christina M. Kochel","orcid":null,"position":8,"is_corresponding":false},{"id":272254,"name":"Mohamad E. Allaf","orcid":"0000-0003-3333-3904","position":9,"is_corresponding":false},{"id":430621,"name":"Trinity J. Bivalacqua","orcid":"0000-0002-0870-4366","position":10,"is_corresponding":false},{"id":242992,"name":"Michael Lim","orcid":"0000-0003-0523-3076","position":11,"is_corresponding":false},{"id":465009,"name":"Charles Karan","orcid":"0000-0003-4012-8677","position":12,"is_corresponding":false},{"id":59423,"name":"Charles G. Drake","orcid":"0000-0001-9610-3677","position":13,"is_corresponding":false},{"id":19046,"name":"Andrea Califano","orcid":"0000-0003-4742-3679","position":14,"is_corresponding":false},{"id":266898,"name":"Aleksandar Obradović","orcid":"0000-0002-8009-0186","position":0,"is_corresponding":true}],"reference_count":72,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:31:31.270564Z","pmid":null,"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":[]}