Cyclooxygenase-2 Blockade Is Crucial to Restore Natural Killer Cell Activity before Anti-CTLA-4 Therapy against High-Grade Serous Ovarian Cancer.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38201508", "kind": "science-record", "revision": 3, "content_hash": "sha256:bc8724d0cf937bda21b4d6be845e268c08533e6272c87037ef3d2c140a18aa0f", "created_at": "2026-11-01T19:20:07Z", "updated_at": "2026-11-01T22:11:00Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Cyclooxygenase-2 Blockade Is Crucial to Restore Natural Killer Cell Activity before Anti-CTLA-4 Therapy against High-Grade Serous Ovarian Cancer.", "doi": "10.3390/cancers16010080", "pmid": "38201508", "authors": ["Fernán Gómez-Valenzuela", "Ignacio Wichmann", "Felipe Suárez", "Sumie Kato", "Enrique Ossandón", "Marcela Hermoso", "Elmer A Fernández", "Mauricio A Cuello"], "journal": "Cancers", "year": 2023, "abstract": "Chronic inflammation influences the tumor immune microenvironment (TIME) in high-grade serous ovarian cancer (HGSOC). Specifically, cyclooxygenase-2 (COX-2) overexpression promotes cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) expression. Notably, elevated COX-2 levels in the TIME have been associated with reduced response to anti-CTLA-4 immunotherapy. However, the precise impact of COX-2, encoded by PTGS2, on the immune profile remains unknown. To address this, we performed an integrated bioinformatics analysis using data from the HGSOC cohorts (TCGA-OV, n = 368; Australian cohort AOCS, n = 80; GSE26193, n = 62; and GSE30161, n = 45). Employing Gene Set Variation Analysis (GSVA), MIXTURE and Ecotyper cell deconvolution algorithms, we concluded that COX-2 was linked to immune cell ecosystems associated with shorter survival, cell dysfunction and lower NK cell effector cytotoxicity capacity. Next, we validated these results by characterizing circulating NK cells from HGSOC patients through flow cytometry and cytotoxic assays while undergoing COX-2 and CTLA-4 blockade. The blockade of COX-2 improved the cytotoxic capacity of NK cells against HGSOC cell lines. Our findings underscore the relevance of COX-2 in shaping the TIME and suggest its potential as a prognostic indicator and therapeutic target. Increased COX-2 expression may hamper the effectivity of immunotherapies that require NK cell effector function. These results provide a foundation for experimental validation and clinical trials investigating combined therapies targeting COX-2 and CTLA-4 in HGSOC.", "claims": [{"id": "claim-method", "statement": "To build up the survival curves (using progression-free survival [PFS] as the primary clinical outcome), we used the KM plotter Survival Analysis Tool [30], considering the ratio of the prostaglandin-endoperoxide synthase 2, PTGS2 (the COX-2 gene) and CTLA4, and defined survival according to the median-based PTGS2/CTLA4 cutoff. Univariate/multivariate Cox proportional hazard regression analyses were performed for all variables using the ‘coxph’ function from the survival R package version 3.5–5.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38201508", "locator": "sections[4] \"2.2. Genetic Assessment of COX-2, CTLA-4, and Ovarian Tumor Immune Microenvironment\" paragraph 2", "quote": "To build up the survival curves (using progression-free survival [PFS] as the primary clinical outcome), we used the KM plotter Survival Analysis Tool [30], considering the ratio of the prostaglandin-endoperoxide synthase 2, PTGS2 (the COX-2 gene) and CTLA4, and defined survival according to the median-based PTGS2/CTLA4 cutoff."}, {"asset": "source:pmid:38201508", "locator": "sections[11] \"2.9. Statistical Analyses\" paragraph 2", "quote": "Univariate/multivariate Cox proportional hazard regression analyses were performed for all variables using the ‘coxph’ function from the survival R package version 3.5–5."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38201508", "locator": "sections[24] \"Data Availability Statement\" paragraph 2", "quote": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": null, "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38201508"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE26193"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE26193"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:38201508", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3390/cancers16010080", "sha256": "sha256:ac27a9a2c6118ae7a6c2920b06eb1005ffcf07f13e24b4b321dee0e97642b4de", "bytes": 57558, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3390/cancers16010080", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC10778357", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE26193", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE26193", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE26193", "version": null, "note": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023).", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023).", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM642933", "GSM642934", "GSM642935", "GSM642936", "GSM642937", "GSM642938", "GSM642939", "GSM642940", "GSM642941", "GSM642942", "GSM642943", "GSM642944", "GSM642945", "GSM642946", "GSM642947", "GSM642948", "GSM642949", "GSM642950", "GSM642951", "GSM642952", "GSM642953", "GSM642954", "GSM642955", "GSM642956", "GSM642957", "GSM642958", "GSM642959", "GSM642960", "GSM642961", "GSM642962", "GSM642963", "GSM642964", "GSM642965", "GSM642966", "GSM642967", "GSM642968", "GSM642969", "GSM642970", "GSM642971", "GSM642972", "GSM642973", "GSM642974", "GSM642975", "GSM642976", "GSM642977", "GSM642978", "GSM642979", "GSM642980", "GSM642981", "GSM642982", "GSM642983", "GSM642984", "GSM642985", "GSM642986", "GSM642987", "GSM642988", "GSM642989", "GSM642990", "GSM642991", "GSM642992", "GSM642993", "GSM642994", "GSM642995", "GSM642996", "GSM642997", "GSM642998", "GSM642999", "GSM643000", "GSM643001", "GSM643002", "GSM643003", "GSM643004", "GSM643005", "GSM643006", "GSM643007", "GSM643008", "GSM643009", "GSM643010", "GSM643011", "GSM643012", "GSM643013", "GSM643014", "GSM643015", "GSM643016", "GSM643017", "GSM643018", "GSM643019", "GSM643020", "GSM643021", "GSM643022", "GSM643023", "GSM643024", "GSM643025", "GSM643026", "GSM643027", "GSM643028", "GSM643029", "GSM643030", "GSM643031", "GSM643032", "GSM643033", "GSM643034", "GSM643035", "GSM643036", "GSM643037", "GSM643038", "GSM643039"], "sample_count": 107, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Control of oxidative stress by miRNA and impact on ovarian tumorigenesis", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE30161", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE30161", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE30161", "version": null, "note": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023).", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023).", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM746861", "GSM746862", "GSM746863", "GSM746864", "GSM746865", "GSM746866", "GSM746867", "GSM746868", "GSM746869", "GSM746870", "GSM746871", "GSM746872", "GSM746873", "GSM746874", "GSM746875", "GSM746876", "GSM746877", "GSM746878", "GSM746879", "GSM746880", "GSM746881", "GSM746882", "GSM746883", "GSM746884", "GSM746885", "GSM746886", "GSM746887", "GSM746888", "GSM746889", "GSM746890", "GSM746891", "GSM746892", "GSM746893", "GSM746894", "GSM746895", "GSM746896", "GSM746897", "GSM746898", "GSM746899", "GSM746900", "GSM746901", "GSM746902", "GSM746903", "GSM746904", "GSM746905", "GSM746906", "GSM746907", "GSM746908", "GSM746909", "GSM746910", "GSM746911", "GSM746912", "GSM746913", "GSM746914", "GSM746915", "GSM746916", "GSM746917", "GSM746918"], "sample_count": 58, "group_sizes": null, "group_sizes_basis": null, "platform": "570", "taxon": "Homo sapiens", "title": "Genomic Multivariate Predictors of Response to Adjuvant Chemotherapy in Ovarian Carcinoma: Predicting Platinum Resistance", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE26193 not downloaded", "asset:data:geo:GSE26193 licence not read", "asset:data:geo:GSE30161 not downloaded", "asset:data:geo:GSE30161 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "survival_analysis", "specific": "cox_proportional_hazards", "label": "Survival analysis", "dsl_operations": ["cox_ph"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 1.0, "band": "reordered", "quote": "To build up the survival curves (using progression-free survival [PFS] as the primary clinical outcome), we used the KM plotter Survival Analysis Tool [30], considering the ratio of the prostaglandin-endoperoxide synthase 2, PTGS2 (the COX-2 gene) and CTLA4, and defined survival according to the median-based PTGS2/CTLA4 cutoff. Univariate/multivariate Cox proportional hazard regression analyses were performed for all variables using the ‘coxph’ function from the survival R package version 3.5–5."}}, {"id": "method-2", "family": "group_comparison", "specific": "welch_t_test", "label": "Group comparison", "dsl_operations": ["welch_t"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "Welch"}}, {"id": "method-3", "family": "survival_analysis", "specific": "kaplan_meier", "label": "Survival analysis", "dsl_operations": ["survival_km"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["time_to_event_with_censoring"], "evidence": {"score": 0.8, "band": "high", "quote": "KM"}}, {"id": "method-4", "family": "flow_cytometry_analysis", "specific": "mfi", "label": "Flow cytometry analysis", "dsl_operations": ["gate_population", "quantify_mfi", "compensation_matrix"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["event_table"], "evidence": {"score": 0.8, "band": "high", "quote": "MFI"}}], "targets": [], "gaps": ["method.reader_differs_from_extractor"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["cox_ph"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: cox_proportional_hazards."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE26193", "GSE30161"], "resolved_accessions": ["GSE26193", "GSE30161"], "statements": ["Transcript per Million (TPM) RNA-seq expression and clinical data can be accessed and downloaded from Genomic Data Commons through the TCGA-biolinks R package and ICGC Data Portal for the AOCS cohort. Lastly, normalized RNA array data were downloaded from https://www.refine.bio/website (accessed on 20 July 2023)."], "basis": "The paper names GSE26193, GSE30161 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["cox_ph"], "assets": ["source:pmid:38201508", "data:geo:GSE26193"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE26193"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:04:54Z", "independence": "single_reader"}, "evidence_check": {"method": "reordered", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 17198, "completion_tokens": 2371, "cached_tokens": 128}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:38201508", "type": "paper", "label": "pmid:38201508"}, {"id": "source:pmid:38201508", "type": "manuscript", "label": "PMID 38201508 full text"}, {"id": "data:geo:GSE26193", "type": "dataset", "label": "GEO GSE26193"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:38201508", "type": "paper", "label": "pmid:38201508"}, {"id": "source:pmid:38201508", "type": "manuscript", "label": "PMID 38201508 full text"}, {"id": "data:geo:GSE26193", "type": "dataset", "label": "GEO GSE26193"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-38201508", "type": "extraction", "used": ["source:pmid:38201508"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE26193", "type": "accession_resolution", "used": ["data:geo:GSE26193"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:38201508", "parent_hash": "sha256:caa3ee7a9f9ae75dd85e389747cc8f5b900d4edfcb2699dca7736aaeaaefea7b", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE26193 licence not read", "asset:data:geo:GSE26193 not downloaded", "asset:data:geo:GSE30161 licence not read", "asset:data:geo:GSE30161 not downloaded", "execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "flow_cytometry", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ulating NK cells from HGSOC patients through flow cytometry and cytotoxic assays while undergoing COX-2"], "order_basis": "paper_text_order:1112", "id": "assay:1"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["er’s recommendations. Isolated NK cells were cultured in 24-well treated clear plates (3526, Costar C", "m, and 50 μL or 500 IU of IL-2 (1 mg/mL). We cultured human cancer cell lines HeyA8 kindly donated"], "order_basis": "paper_text_order:2366", "id": "assay:2"}, {"role": "analysis", "definition_id": "survival_analysis", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["cox_ph"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["To build up the survival curves (using progression-free survival [PFS] as the primary clinical outcome), we used the KM plotter Survival Analysis Tool [30], considering the ratio of the prostaglandin-endoperoxide synthase 2, PTGS2 (the COX-2 gene) and CTLA4, and defined survival according to the median-based PTGS2/CTLA4 cutoff. Univariate/multivariate Cox proportional hazard regression analyses were performed for all variables using the ‘coxph’ function from the survival R package version 3.5–5."], "order_basis": "consumes_earlier_output", "id": "assay:3"}]}