{"doi":"10.1101/2023.12.18.572239","title":"Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease","abstract":"Leptomeningeal disease (LMD) occurs when tumors seed into the leptomeningeal space and cerebrospinal fluid (CSF), leading to severe neurological deterioration and poor survival outcomes. We utilized comprehensive multi-omics analyses of CSF from patients with lymphoma LMD to demonstrate an immunosuppressive cellular microenvironment and identified dysregulations in proteins and lipids indicating neurodegenerative processes. Strikingly, we found a significant accumulation of toxic branched-chain keto acids (BCKA) in the CSF of patients with LMD. The BCKA accumulation was found to be a pan-cancer occurrence, evident in lymphoma, breast cancer, and melanoma LMD patients. Functionally, BCKA disrupted the viability and function of endogenous T lymphocytes, chimeric antigen receptor (CAR) T cells, neurons, and meningeal cells. Treatment of LMD mice with BCKA-reducing sodium phenylbutyrate significantly improved neurological function, survival outcomes, and efficacy of anti-CD19 CAR T cell therapy. This is the first report of BCKA accumulation in LMD and provides preclinical evidence that targeting these toxic metabolites improves outcomes.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401990,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9495,"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":1179366,"name":"Yuan Ren","orcid":"0000-0001-5857-9535","position":1,"is_corresponding":false},{"id":935678,"name":"Ronak Kundalia","orcid":"0000-0002-1287-7120","position":2,"is_corresponding":false},{"id":1179367,"name":"Hasan Alhaddad","orcid":"0000-0001-7904-2913","position":3,"is_corresponding":false},{"id":564625,"name":"Zhihua Chen","orcid":"0000-0002-4390-7636","position":4,"is_corresponding":false},{"id":922068,"name":"Gerald Wallace","orcid":null,"position":5,"is_corresponding":false},{"id":327299,"name":"Brittany Evernden","orcid":null,"position":6,"is_corresponding":false},{"id":663573,"name":"Oscar E. Ospina","orcid":"0000-0001-5986-4207","position":7,"is_corresponding":false},{"id":692356,"name":"MacLean Hall","orcid":"0000-0002-5626-1619","position":8,"is_corresponding":false},{"id":310322,"name":"Min Liu","orcid":"0000-0002-1626-7100","position":9,"is_corresponding":false},{"id":226773,"name":"Lancia Darville","orcid":"0000-0002-9793-3741","position":10,"is_corresponding":false},{"id":489130,"name":"Victoria Izumi","orcid":"0000-0001-6467-9081","position":11,"is_corresponding":false},{"id":403075,"name":"Y. Ann Chen","orcid":"0000-0003-1468-3490","position":12,"is_corresponding":false},{"id":242938,"name":"Shari Pilon‐Thomas","orcid":"0000-0001-7785-3034","position":13,"is_corresponding":false},{"id":63492,"name":"Paul Allen Stewart","orcid":"0000-0003-0882-308X","position":14,"is_corresponding":false},{"id":226778,"name":"John M. Koomen","orcid":"0000-0002-3818-1762","position":15,"is_corresponding":false},{"id":1179368,"name":"Salvatore Corallo","orcid":"0009-0001-2450-4022","position":16,"is_corresponding":false},{"id":108395,"name":"Michael D. Jain","orcid":"0000-0002-7789-1257","position":17,"is_corresponding":false},{"id":491681,"name":"Timothy J. Robinson","orcid":"0000-0003-0021-0668","position":18,"is_corresponding":false},{"id":1179699,"name":"Fredrick L. Locke","orcid":null,"position":19,"is_corresponding":false},{"id":225601,"name":"Peter Forsyth","orcid":"0000-0002-3756-8594","position":20,"is_corresponding":false},{"id":325114,"name":"Inna Smalley","orcid":"0000-0002-6796-9145","position":21,"is_corresponding":false},{"id":1063712,"name":"Mariam Lotfy Khaled","orcid":"0009-0009-2088-3801","position":0,"is_corresponding":true}],"reference_count":96,"raw_metadata":null,"created_at":"2026-07-19T01:20:23.920156Z","pmid":"38187773","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":[]}