{"doi":"10.1007/s11060-025-04978-2","title":"Improving IL12 immunotherapy in glioblastoma by targeting the long noncoding RNA INCR1","abstract":"PURPOSE: The potent antitumor effects of interleukin 12 (IL12) gene therapy in glioblastoma (GBM) are significantly attenuated by the highly immunosuppressive microenvironment and the upregulation of the PD-1/PD-L1 immune checkpoint. However, combining IL12 gene therapy with PD-1/PD-L1 inhibitors failed to improve efficacy. This study aims to assess the effects of silencing the immunosuppressive long noncoding RNA INCR1 when combined with IL12 therapy. METHODS: RNAscope in situ hybridization was performed to analyze INCR1 and PD-L1 expression in tumor tissues from GBM patients pre- and post-IL12 gene therapy. Quantitative PCR was used to analyze immunosuppressive gene expression in patient-derived GBM cells co-cultured with immune cells stimulated with IL12. The effects of INCR1 and PD-L1 silencing on the expression of immunosuppressive genes were evaluated by RNA sequencing. 3D-cytotoxicity assays were performed to assess the activity of immune cells against GBM tumor cells. RESULTS: INCR1 and PD-L1 expression was upregulated in tumor tissue from GBM patients treated with IL12 gene therapy compared to the tumor tissue of the same patients before the IL12 treatment. Co-culture of patient-derived GBM cells with IL12-stimulated immune cells increased the expression of several immunosuppressive genes. Knocking down INCR1 was more effective than silencing PD-L1 in reducing the expression of multiple immunosuppressive genes. INCR1 silencing improved IL12-mediated immune cell antitumor activity compared to monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint signaling. CONCLUSION: INCR1 silencing affects more immune evasive pathways than PD-L1. Targeting INCR1 may represent a valid approach to improve the efficacy of IL12 therapy in GBM.","journal":"Journal of Neuro-Oncology","year":2025,"id":519168,"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":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"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":1029668,"name":"Josephina A.M.A. Gadet","orcid":"0009-0002-0724-385X","position":1,"is_corresponding":false},{"id":4539,"name":"Gordon J. Freeman","orcid":"0000-0002-7210-5616","position":2,"is_corresponding":false},{"id":25289,"name":"E. Antonio Chiocca","orcid":"0000-0001-5183-1670","position":3,"is_corresponding":false},{"id":310563,"name":"Marco Mineo","orcid":"0000-0001-7608-4579","position":4,"is_corresponding":false},{"id":1387039,"name":"Shikha Saini","orcid":"0000-0003-0557-1649","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:49:14.184995Z","pmid":"40035950","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":[]}