{"doi":"10.1007/s00262-023-03530-3","title":"Bis-indole-derived NR4A1 antagonists inhibit colon tumor and splenic growth and T-cell exhaustion","abstract":"There is evidence that the orphan nuclear receptor 4A1 (NR4A1, Nur77) is overexpressed in exhausted CD8 + T cells and regulates PD-L1 in tumors. This study investigated the effects of potent bis-indole-derived NR4A1 antagonists on reversing T-cell exhaustion and downregulating PD-L1 in colon tumors/cells. NR4A1 antagonists inhibited colon tumor growth and downregulated expression of PD-L1 in mouse colon MC-38-derived tumors and cells. TILs from MC-38 cell-derived colon tumors and splenic lymphocytes exhibited high levels of the T-cell exhaustion markers including PD-1, 2B4, TIM3+ and TIGIT and similar results were observed in the spleen, and these were inhibited by NR4A1 antagonists. In addition, treatment with NR4A1 antagonists induced cytokine activation markers interferon γ, granzyme B and perforin mRNAs and decreased TOX, TOX2 and NFAT in TIL-derived CD8 + T cells. Thus, NR4A1 antagonists decrease NR4A1-dependent pro-oncogenic activity and PD-L1 expression in colon tumors and inhibit NR4A1-dependent T-cell exhaustion in TILs and spleen and represent a novel class of mechanism-based drugs that enhance immune surveillance in tumors.","journal":"Cancer Immunology Immunotherapy","year":2023,"id":329047,"datarank":0.4636563680037475,"base_score":3.091042453358316,"endowment":3.091042453358316,"self_citation_contribution":0.4636563680037475,"citation_network_contribution":0.0,"self_endowment_contribution":0.4636563680037475,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":21,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9549,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":461255,"name":"Gus A. Wright","orcid":"0000-0003-4010-7825","position":1,"is_corresponding":false},{"id":330487,"name":"Subhashree Kumaravel","orcid":null,"position":2,"is_corresponding":false},{"id":374293,"name":"Rupesh Shrestha","orcid":"0000-0002-6785-2932","position":3,"is_corresponding":false},{"id":890859,"name":"Lei Zhang","orcid":"0000-0002-7781-3478","position":4,"is_corresponding":false},{"id":356840,"name":"Maen Abdelrahim","orcid":"0000-0002-6631-5035","position":5,"is_corresponding":false},{"id":241898,"name":"Robert S. Chapkin","orcid":"0000-0002-6515-3898","position":6,"is_corresponding":false},{"id":260421,"name":"Stephen Safe","orcid":"0000-0002-2115-3060","position":7,"is_corresponding":false},{"id":375376,"name":"Kumaravel Mohankumar","orcid":null,"position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:08:56.940647Z","pmid":"37847301","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":[]}