Lactate Dehydrogenase A Depletion Alters MyC-CaP Tumor Metabolism, Microenvironment, and CAR T Cell Therapy

Mayuresh M. Mane, Ivan J. Cohen, Ellen Ackerstaff, Khalid Shalaby, Jenny N. Ijoma, Myat Ko, Masatomo Maeda, Avi S. Albeg, Kiranmayi Vemuri, Jaya Satagopan, Anna Moroz, Juan Zurita, Larissa Shenker, Masahiro Shindo, Tanner Nickles, Ekaterina Nikolov, Maxim A. Moroz, Jason A. Koutcher, Inna Serganova, Vladimir PonomarevRonald G. Blasberg

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)382-395
Number of pages14
JournalMolecular Therapy - Oncolytics
Volume18
DOIs
StatePublished - Sep 25 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Oncology
  • Cancer Research
  • Pharmacology (medical)

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

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