{"doi":"10.1101/2023.12.21.572867","title":"Spatial analysis of NOS2 and COX2 interaction with T-effector cells reveals immunosuppressive landscapes associated with poor outcome in ER- breast cancer patients","abstract":"Multiple immunosuppressive mechanisms exist in the tumor microenvironment that drive poor outcomes and decrease treatment efficacy. The co-expression of NOS2 and COX2 is a strong predictor of poor prognosis in ER- breast cancer and other malignancies. Together, they generate pro-oncogenic signals that drive metastasis, drug resistance, cancer stemness, and immune suppression. Using an ER- breast cancer patient cohort, we found that the spatial expression patterns of NOS2 and COX2 with CD3+CD8+PD1- T effector (Teff) cells formed a tumor immune landscape that correlated with poor outcome. NOS2 was primarily associated with the tumor-immune interface, whereas COX2 was associated with immune desert regions of the tumor lacking Teff cells. A higher ratio of NOS2 or COX2 to Teff was highly correlated with poor outcomes. Spatial analysis revealed that regional clustering of NOS2 and COX2 was associated with stromal-restricted Teff, while only COX2 was predominant in immune deserts. Examination of other immunosuppressive elements, such as PDL1/PD1, Treg, B7H4, and IDO1, revealed that PDL1/PD1, Treg, and IDO1 were primarily associated with restricted Teff, whereas B7H4 and COX2 were found in tumor immune deserts. Regardless of the survival outcome, other leukocytes, such as CD4 T cells and macrophages, were primarily in stromal lymphoid aggregates. Finally, in a 4T1 model, COX2 inhibition led to a massive cell infiltration, thus validating the hypothesis that COX2 is an essential component of the Teff exclusion process and, thus, tumor evasion. Our study indicates that NOS2/COX2 expression plays a central role in tumor immunosuppression. Our findings indicate that new strategies combining clinically available NOS2/COX2 inhibitors with various forms of immune therapy may open a new avenue for the treatment of aggressive ER-breast cancers.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":397985,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9479,"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":428816,"name":"Robert Y.S. Cheng","orcid":"0000-0003-0287-6439","position":1,"is_corresponding":false},{"id":325966,"name":"William F. Heinz","orcid":"0000-0002-6194-0536","position":2,"is_corresponding":false},{"id":896638,"name":"Milind Pore","orcid":null,"position":3,"is_corresponding":false},{"id":1071259,"name":"Ana L. González","orcid":null,"position":4,"is_corresponding":false},{"id":1070796,"name":"Elise L. Femino","orcid":"0000-0001-9490-1093","position":5,"is_corresponding":false},{"id":1174171,"name":"Rebecca Moffat","orcid":"0000-0003-2120-9586","position":6,"is_corresponding":false},{"id":896637,"name":"Adelaide L. Wink","orcid":null,"position":7,"is_corresponding":false},{"id":1174448,"name":"Fatima Imtiaz","orcid":null,"position":8,"is_corresponding":false},{"id":1070797,"name":"Leandro L. Coutinho","orcid":"0000-0002-0989-6144","position":9,"is_corresponding":false},{"id":497095,"name":"Donna Butcher","orcid":"0000-0002-2065-8067","position":10,"is_corresponding":false},{"id":279369,"name":"Elijah F. Edmondson","orcid":"0000-0002-6106-3705","position":11,"is_corresponding":false},{"id":698204,"name":"María Cristina Rangel","orcid":"0000-0002-8002-9617","position":12,"is_corresponding":false},{"id":97864,"name":"Stephen T.C. Wong","orcid":"0000-0001-9188-6502","position":13,"is_corresponding":false},{"id":242501,"name":"Stanley Lipkowitz","orcid":"0000-0002-6103-2255","position":14,"is_corresponding":false},{"id":689799,"name":"Sharon A. Glynn","orcid":"0000-0003-1459-2580","position":15,"is_corresponding":false},{"id":782572,"name":"Michael P. Vitek","orcid":"0000-0001-8140-8048","position":16,"is_corresponding":false},{"id":228149,"name":"Daniel W. McVicar","orcid":"0000-0002-1112-5111","position":17,"is_corresponding":false},{"id":300997,"name":"Xiaoxian Li","orcid":"0000-0002-0995-1721","position":18,"is_corresponding":false},{"id":262407,"name":"Stephen K. Anderson","orcid":"0000-0002-7856-4266","position":19,"is_corresponding":false},{"id":383581,"name":"Nazareno Paolocci","orcid":"0000-0001-7011-997X","position":20,"is_corresponding":false},{"id":237304,"name":"Stephen M. Hewitt","orcid":"0000-0001-8283-1788","position":21,"is_corresponding":false},{"id":130771,"name":"Stefan Ambs","orcid":"0000-0001-7651-9309","position":22,"is_corresponding":false},{"id":246951,"name":"Timothy R. Billiar","orcid":"0000-0002-2949-0811","position":23,"is_corresponding":false},{"id":276042,"name":"Jenny C. Chang","orcid":"0000-0002-0890-9302","position":24,"is_corresponding":false},{"id":317886,"name":"Stephen Lockett","orcid":"0000-0002-2010-9914","position":25,"is_corresponding":false},{"id":228148,"name":"David A. Wink","orcid":"0000-0002-5652-7480","position":26,"is_corresponding":false},{"id":428819,"name":"Lisa A. Ridnour","orcid":"0000-0001-9446-8349","position":0,"is_corresponding":true}],"reference_count":97,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","pmid":"38187660","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":[]}