{"doi":"10.1101/2020.05.11.086371","title":"Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity","abstract":"Abstract Mutant isocitrate-dehydrogenase-1 (IDH1-R132H; mIDH1) is a hallmark of adult gliomas. Lower grade mIDH1 gliomas are classified into two molecular subgroups: (i) 1p/19q co-deletion/TERT-promoter mutations or (ii) inactivating mutations in α-thalassemia/mental retardation syndrome X-linked ( ATRX ) and TP53. This work, relates to the gliomas’ subtype harboring mIDH1, TP53 and ATRX inactivation. IDH1-R132H is a gain-of-function mutation that converts α-ketoglutarate into 2-hydroxyglutarate (D-2HG). The role of D-2HG within the tumor microenvironment of mIDH1/mATRX/mTP53 gliomas remains unexplored. Inhibition of 2HG, when used as monotherapy or in combination with radiation and temozolomide (IR/TMZ), led to increased median survival (MS) of mIDH1 glioma bearing mice. Also, 2HG inhibition elicited anti-mIDH1 glioma immunological memory. In response to 2HG inhibition, PD-L1 expression levels on mIDH1-glioma cells increased to similar levels as observed in wild-type-IDH1 gliomas. Thus, we combined 2HG inhibition/IR/TMZ with anti-PDL1 immune checkpoint-blockade and observed complete tumor regression in 60% of mIDH1 glioma bearing mice. This combination strategy reduced T-cell exhaustion and favored the generation of memory CD8 + T-cells. Our findings demonstrate that metabolic reprogramming elicits anti-mIDH1 glioma immunity, leading to increased MS and immunological memory. Our preclinical data supports the testing of IDH-R132H inhibitors in combination with IR/TMZ and anti-PDL1 as targeted therapy for mIDH1/mATRX/mTP53 glioma patients. Brief Summary Inhibition of 2-Hydroxyglutrate in mutant-IDH1 glioma in the genetic context of ATRX and TP53 inactivation elicits metabolic-reprograming and anti-glioma immunity.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123671,"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":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9544,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":392869,"name":"Stephen V. Carney","orcid":"0000-0001-7786-5158","position":1,"is_corresponding":false},{"id":394103,"name":"Jessica C. Gauss","orcid":null,"position":2,"is_corresponding":false},{"id":392871,"name":"María Belén Garcia-Fabiani","orcid":"0000-0002-2824-4926","position":3,"is_corresponding":false},{"id":352781,"name":"Felipe J. Núñez","orcid":"0000-0002-4962-3642","position":4,"is_corresponding":false},{"id":389691,"name":"Fernando M. Núñez","orcid":null,"position":5,"is_corresponding":false},{"id":394607,"name":"Mahmoud S. Alghamri","orcid":"0000-0002-8018-7674","position":6,"is_corresponding":false},{"id":567033,"name":"Yayuan Liu","orcid":"0000-0001-8287-4737","position":7,"is_corresponding":false},{"id":357091,"name":"Minzhi Yu","orcid":"0000-0002-3141-7285","position":8,"is_corresponding":false},{"id":567034,"name":"Dan Li","orcid":"0000-0002-5567-6927","position":9,"is_corresponding":false},{"id":394105,"name":"Marta Edwards","orcid":null,"position":10,"is_corresponding":false},{"id":249124,"name":"James J. Moon","orcid":"0000-0003-2238-2372","position":11,"is_corresponding":false},{"id":298046,"name":"Anna Schwendeman","orcid":"0000-0002-8023-8080","position":12,"is_corresponding":false},{"id":236218,"name":"Pedro R. Löwenstein","orcid":"0000-0002-8427-4409","position":13,"is_corresponding":false},{"id":394106,"name":"Maria G. Castro","orcid":null,"position":14,"is_corresponding":false},{"id":236214,"name":"Padma Kadiyala","orcid":"0000-0002-3273-9905","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-18T23:15:03.403566Z","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":[]}