Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.

Autor:	Khaled ML; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt., Ren Y; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Kundalia R; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Alhaddad H; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Chen Z; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Wallace GC; Department of Hematology/Oncology, Georgia Cancer Center at Medical College of Georgia, Augusta, GA, USA., Evernden B; Department of Neuro Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Ospina OE; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Hall M; Department of Immunology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Liu M; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Darville LNF; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Izumi V; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Chen YA; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Pilon-Thomas S; Department of Immunology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Stewart PA; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Koomen JM; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.; Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Corallo SA; Department of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Jain MD; Department of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Robinson TJ; Therapeutic Radiology, Smilow Cancer Hospital at Yale New Haven, 35 Park Street, New Haven, CT, USA., Locke FL; Department of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Forsyth PA; Department of Neuro Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.; The Department of Tumor Biology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA., Smalley I; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Dec 18. Date of Electronic Publication: 2023 Dec 18.
DOI:	10.1101/2023.12.18.572239
Abstrakt:	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. Competing Interests: IS, MLK, YR, RK, OO, HA, TR, BE, GCW, ZC, YAC, ML, LNFD, SAC, PAS, and VI declare no relevant conflicts of interest. MDJ would like to disclose consultancy for Kite/Gilead and Novartis and research funding from Kite/Gilead, Incyte, and Loxo@Lilly. PAF would like to disclose consultancy with AbbVie Inc., Bristol-Myers Squibb, Boehringer-Ingelheim, NCI Neuro-Oncology Branch Peer Review, NCRI, NIH, Novellus, Physical Sciences Oncology Network, Tocagen (not active), Ziopharm, National Brain Tumor Society. He is also on the advisory board for Bayer, BTG, GlaxoSmithKline (GSK), Inovio, Novocure, AnHeart Therapeutics, and Midatech. MH would like to disclose that Moffitt Cancer Center has licensed Intellectual Property (IP) related to the proliferation and expansion of tumor-infiltrating lymphocytes (TILs) to Iovance Biotherapeutics. MH is a co-inventor on such Intellectual Property. MH reports common stock holdings in AbbVie, Inc., Amgen, Inc., BioHaven Pharmaceuticals, and Bristol Myers Squibb. SPT would like to disclose that Moffitt Cancer Center has licensed Intellectual Property (IP) related to the proliferation and expansion of tumor-infiltrating lymphocytes (TILs) to Iovance Biotherapeutics. Moffitt has also licensed IP to Tuhura Biopharma. Dr. Pilon-Thomas (SPT) is an inventor on such Intellectual Property. SPT is listed as a co-inventor on a patent application with Provectus Biopharmaceuticals. SPT participates in sponsored research agreements with Provectus Biopharmaceuticals, Iovance Biotherapeutics, Intellia Therapeutics, Dyve Biosciences, Turnstone Biologics, and Celgene that are not related to this research. SPT has received research support that is not related to this research from the following entities: NIHNCI, DOD, Swim Across America, the V Foundation, and The Mark Foundation for Cancer Research. SPT has received consulting fees from Seagen Inc., Morphogenesis, Inc., and KSQ Therapeutics. FLL would like to disclose the following: Scientific Advisory Role/Consulting Fees: A2, Allogene, Amgen, Bluebird Bio, BMS, Calibr, Caribou, Cowen, EcoR1, Gerson Lehrman Group (GLG), Iovance, Kite Pharma, Janssen, Legend Biotech, Novartis, Sana, Umoja, Pfizer. Data Safety Monitoring Board: Data and Safety Monitoring Board for the NCI Safety Oversight CAR T-cell Therapies Committee. Research Contracts or Grants to my Institution for Service: Kite Pharma (Institutional), Allogene (Institutional), CERo Therapeutics (Institutional), Novartis (Institutional), BlueBird Bio (Institutional), 2SeventyBio (Institutional), BMS (Institutional), National Cancer Institute (R01CA244328 MPI: Locke; P30CA076292 PI: Cleveland), Leukemia and Lymphoma Society Scholar in Clinical Research (PI: Locke). Patents, Royalties, Other Intellectual Property: Several patents held by the institution in my name (unlicensed) in the field of cellular immunotherapy. Education or Editorial Activity: Aptitude Health, ASH, BioPharma Communications CARE Education, Clinical Care Options Oncology, Imedex, Society for Immunotherapy of Cancer
Databáze:	MEDLINE
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