Lactate dehydrogenase a depletion alters MyC-CaP tumor metabolism, microenvironment, and CAR T cell therapy Journal Article
| Authors: | Mane, M. M.; Cohen, I. J.; Ackerstaff, E.; Shalaby, K.; Ijoma, J. N.; Ko, M.; Maeda, M.; Albeg, A. S.; Vemuri, K.; Satagopan, J.; Moroz, A.; Zurita, J.; Shenker, L.; Shindo, M.; Nickles, T.; Nikolov, E.; Moroz, M. A.; Koutcher, J. A.; Serganova, I.; Ponomarev, V.; Blasberg, R. G. |
| Article 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. © 2020 The Authors Mane et al. achieved LDH-A depletion in hPSMA+ MyC-CaP prostate tumor cells, resulting in decreased glycolysis, lactate production, and tumor cell proliferation. In vivo, LDH-A-depleted tumors treated with anti-hPSMA CAR T cells grew significantly slower than did control tumors, and the dominant treatment effect was due to LDH-A depletion. © 2020 The Authors |
| Keywords: | controlled study; treatment response; nonhuman; t cells; antigen expression; animal cell; mouse; animal tissue; green fluorescent protein; animal experiment; animal model; prostate cancer; prostate specific membrane antigen; prostate tumor; tumor cell; magnetic resonance spectroscopy; chimeric antigen receptor; down regulation; tumor model; tumor growth; tumor vascularization; cell metabolism; short hairpin rna; depletion; renilla luciferin 2 monooxygenase; lactic acid; tumor microenvironment; bioluminescence imaging; tumor blood flow; mrs; tumor metabolism; internal ribosome entry site; lactate; bli; car; male; priority journal; article; lactate dehydrogenase a; luciferase reporters; 4t1 cell line; chimeric antigen receptor t-cell immunotherapy; ldh-a; hpsma; human prostate-specific membrane antigen; tme |
| Journal Title: | Molecular Therapy - Oncolytics |
| Volume: | 18 |
| ISSN: | 2372-7705 |
| Publisher: | Cell Press |
| Date Published: | 2020-09-25 |
| Start Page: | 382 |
| End Page: | 395 |
| Language: | English |
| DOI: | 10.1016/j.omto.2020.07.006 |
| PROVIDER: | scopus |
| PMCID: | PMC7452096 |
| PUBMED: | 32913888 |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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