@article{79f2f2221a954cd8a15f371b193e902c,
title = "Lactate Dehydrogenase A Depletion Alters MyC-CaP Tumor Metabolism, Microenvironment, and CAR T Cell Therapy",
abstract = "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.",
keywords = "BLI, CAR, LDH-A, MRS, T cells, TME, bioluminescence imaging, chimeric antigen receptor, hPSMA, human prostate-specific membrane antigen, lactate, lactate dehydrogenase A, luciferase reporters, magnetic resonance spectroscopy, prostate cancer, tumor metabolism, tumor microenvironment",
author = "Mane, {Mayuresh M.} and Cohen, {Ivan J.} and Ellen Ackerstaff and Khalid Shalaby and Ijoma, {Jenny N.} and Myat Ko and Masatomo Maeda and Albeg, {Avi S.} and Kiranmayi Vemuri and Jaya Satagopan and Anna Moroz and Juan Zurita and Larissa Shenker and Masahiro Shindo and Tanner Nickles and Ekaterina Nikolov and Moroz, {Maxim A.} and Koutcher, {Jason A.} and Inna Serganova and Vladimir Ponomarev and Blasberg, {Ronald G.}",
note = "Funding Information: We thank Dr. Hanwen Zhang, Dr. Naga Vara Kishore Pillarsetty, and Blesida Punzalan for advice and technical assistance. We acknowledge the Molecular Cytology Core Facility of MSKCC, especially Dr. K. Manova-Todorova and D. Yarilin, for scientific and technical advice. We also thank the Department of Radiology of MSKCC for support. We thank Dr. D. Shungu and X. Mao (Cornell University) for the MR analysis software XsOsNMR. This work was supported by NIH grants R01 CA163980, R01 CA204924, R01 CA215136 (to R.G.B.); P30 CA008748 (MSK Cancer Center Support Grant/Core Grant); R50 CA221810 (to I.S.); R01 CA220524-01A1 and R21 CA213139 01A1 (to V.P.); and DOD BCRP BC161705 and the Breast and Molecular Imaging Fund, Evelyn H. Lauder Breast Center (to J.A.K.). Funding Information: We thank Dr. Hanwen Zhang, Dr. Naga Vara Kishore Pillarsetty, and Blesida Punzalan for advice and technical assistance. We acknowledge the Molecular Cytology Core Facility of MSKCC, especially Dr. K. Manova-Todorova and D. Yarilin, for scientific and technical advice. We also thank the Department of Radiology of MSKCC for support. We thank Dr. D. Shungu and X. Mao (Cornell University) for the MR analysis software XsOsNMR. This work was supported by NIH grants R01 CA163980 , R01 CA204924 , R01 CA215136 (to R.G.B.); P30 CA008748 ( MSK Cancer Center Support Grant/Core Grant); R50 CA221810 (to I.S.); R01 CA220524-01A1 and R21 CA213139 01A1 (to V.P.); and DOD BCRP BC161705 and the Breast and Molecular Imaging Fund, Evelyn H. Lauder Breast Center (to J.A.K.). Publisher Copyright: {\textcopyright} 2020 The Authors",
year = "2020",
month = sep,
day = "25",
doi = "10.1016/j.omto.2020.07.006",
language = "English (US)",
volume = "18",
pages = "382--395",
journal = "Molecular Therapy - Oncolytics",
issn = "2372-7705",
publisher = "Nature Publishing Group",
}