Lactate Dehydrogenase A Depletion Alters MyC-CaP Tumor Metabolism, Microenvironment, and CAR T Cell Therapy
Mayuresh Mane, Ivan Cohen, Ellen Ackerstaff, Khalid Shalaby, Jenny N. Ijoma, Myat Ko, Masatomo Maeda, Avi S. Albeg, Kiranmayi Vemuri, Jaya M. Satagopan, Anna Moroz, Juan Zurita, Larissa Shenker, Masahiro Shindo, Tanner Nickles, Ekaterina Nikolov, Maxim A. Moroz, Jason A. Koutcher, Inna Serganova, Vladimir Ponomarev, Ronald G. Blasberg
Abstract
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.