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Branched-chain keto acids promote an immune-suppressive and neurodegenerative microenvironment in leptomeningeal disease.
Khaled, Mariam Lotfy; Ren, Yuan; Kundalia, Ronak; Alhaddad, Hasan; Chen, Zhihua; Wallace, Gerald C; Evernden, Brittany; Ospina, Oscar E; Hall, MacLean; Liu, Min; Darville, Lancia N F; Izumi, Victoria; Chen, Y Ann; Pilon-Thomas, Shari; Stewart, Paul A; Koomen, John M; Corallo, Salvatore A; Jain, Michael D; Robinson, Timothy J; Locke, Fredrick L; Forsyth, Peter A; Smalley, Inna.
Afiliación
  • Khaled ML; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Ren Y; Department of Biochemistry, Faculty of Pharmacy, Cairo University, Egypt.
  • 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; The Department of Metabolism and Physiology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Wallace GC; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Evernden B; Department of Hematology/Oncology, Georgia Cancer Center at Medical College of Georgia, Augusta, GA, USA.
  • Ospina OE; Department of Neuro Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Hall M; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Liu M; Department of Immunology, 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; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Pilon-Thomas S; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Stewart PA; Department of Immunology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Koomen JM; Department of Biostatistics and Bioinformatics, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Corallo SA; The Proteomics and Metabolomics Core, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Jain MD; Department of Molecular Oncology, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
  • Robinson TJ; Department of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 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; Therapeutic Radiology, Smilow Cancer Hospital at Yale New Haven, 35 Park Street, New Haven, CT, USA.
  • Smalley I; Department of Blood and Marrow Transplant and Cellular Immunotherapy, The Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
bioRxiv ; 2023 Dec 18.
Article en En | MEDLINE | ID: mdl-38187773
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.
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Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos