Lactate Dehydrogenase A depletion alters MyC-CaP tumor metabolism, microenvironment and CAR T cell therapy

Abstract To enhance hPSMA-specific 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 shRNA knockdown (KD) was achieved in MyC-CaP:hPSMA(+)RLuc-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 knock-down 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