PMID- 32913888 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20200928 IS - 2372-7705 (Print) IS - 2372-7705 (Electronic) IS - 2372-7705 (Linking) VI - 18 DP - 2020 Sep 25 TI - Lactate Dehydrogenase A Depletion Alters MyC-CaP Tumor Metabolism, Microenvironment, and CAR T Cell Therapy. PG - 382-395 LID - 10.1016/j.omto.2020.07.006 [doi] AB - To enhance human prostate-specific membrane antigen (hPSMA)-specific chimeric antigen receptor (CAR) T cell therapy in a hPSMA(+) MyC-CaP tumor model, we studied and imaged the effect of lactate dehydrogenase A (LDH-A) depletion on the tumor microenvironment (TME) and tumor progression. Effective LDH-A short hairpin RNA (shRNA) knockdown (KD) was achieved in MyC-CaP:hPSMA(+) Renilla luciferase (RLuc)-internal ribosome entry site (IRES)-GFP tumor cells, and changes in tumor cell metabolism and in the TME were monitored. LDH-A downregulation significantly inhibited cell proliferation and subcutaneous tumor growth compared to control cells and tumors. However, total tumor lactate concentration did not differ significantly between LDH-A knockdown and control tumors, reflecting the lower vascularity, blood flow, and clearance of lactate from LDH-A knockdown tumors. Comparing treatment responses of MyC-CaP tumors with LDH-A depletion and/or anti-hPSMA CAR T cells showed that the dominant effect on tumor growth was LDH-A depletion. With anti-hPSMA CAR T cell treatment, tumor growth was significantly slower when combined with tumor LDH-A depletion and compared to control tumor growth (p < 0.0001). The lack of a complete tumor response in our animal model can be explained in part by (1) the lower activity of human CAR T cells against hPSMA-expressing murine tumors in a murine host, and (2) a loss of hPSMA antigen from the tumor cell surface in progressive generations of tumor cells. CI - (c) 2020 The Authors. FAU - Mane, Mayuresh M AU - Mane MM AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Cohen, Ivan J AU - Cohen IJ AD - Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Ackerstaff, Ellen AU - Ackerstaff E AD - Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Shalaby, Khalid AU - Shalaby K AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Ijoma, Jenny N AU - Ijoma JN AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Ko, Myat AU - Ko M AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Maeda, Masatomo AU - Maeda M AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Albeg, Avi S AU - Albeg AS AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Vemuri, Kiranmayi AU - Vemuri K AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Satagopan, Jaya AU - Satagopan J AD - Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Moroz, Anna AU - Moroz A AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Skolkovo Institute of Science and Technology, 143026 Moscow, Russia. FAU - Zurita, Juan AU - Zurita J AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Shenker, Larissa AU - Shenker L AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Shindo, Masahiro AU - Shindo M AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Nickles, Tanner AU - Nickles T AD - Gerstner Sloan Kettering Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Nikolov, Ekaterina AU - Nikolov E AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Moroz, Maxim A AU - Moroz MA AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Koutcher, Jason A AU - Koutcher JA AD - Department of Medical Physics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Weill Cornell Medical College, Cornell University, New York, NY 10065, USA. FAU - Serganova, Inna AU - Serganova I AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Ponomarev, Vladimir AU - Ponomarev V AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. FAU - Blasberg, Ronald G AU - Blasberg RG AD - Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. AD - Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. LA - eng GR - R01 CA163980/CA/NCI NIH HHS/United States GR - R21 CA213139/CA/NCI NIH HHS/United States GR - R01 CA220524/CA/NCI NIH HHS/United States GR - R50 CA221810/CA/NCI NIH HHS/United States GR - P30 CA008748/CA/NCI NIH HHS/United States GR - R01 CA204924/CA/NCI NIH HHS/United States GR - R01 CA215136/CA/NCI NIH HHS/United States PT - Journal Article DEP - 20200721 PL - United States TA - Mol Ther Oncolytics JT - Molecular therapy oncolytics JID - 101666776 PMC - PMC7452096 OTO - NOTNLM OT - BLI OT - CAR OT - LDH-A OT - MRS OT - T cells OT - TME OT - bioluminescence imaging OT - chimeric antigen receptor OT - hPSMA OT - human prostate-specific membrane antigen OT - lactate OT - lactate dehydrogenase A OT - luciferase reporters OT - magnetic resonance spectroscopy OT - prostate cancer OT - tumor metabolism OT - tumor microenvironment EDAT- 2020/09/12 06:00 MHDA- 2020/09/12 06:01 PMCR- 2020/07/21 CRDT- 2020/09/11 05:45 PHST- 2020/05/21 00:00 [received] PHST- 2020/07/14 00:00 [accepted] PHST- 2020/09/11 05:45 [entrez] PHST- 2020/09/12 06:00 [pubmed] PHST- 2020/09/12 06:01 [medline] PHST- 2020/07/21 00:00 [pmc-release] AID - S2372-7705(20)30110-8 [pii] AID - 10.1016/j.omto.2020.07.006 [doi] PST - epublish SO - Mol Ther Oncolytics. 2020 Jul 21;18:382-395. doi: 10.1016/j.omto.2020.07.006. eCollection 2020 Sep 25.