TY - JOUR
T1 - Scaffolding LSD1 Inhibitors Impair NK Cell Metabolism and Cytotoxic Function Through Depletion of Glutathione
AU - Bailey, Cavan P.
AU - Figueroa, Mary
AU - Gangadharan, Achintyan
AU - Lee, Dean A.
AU - Chandra, Joya
N1 - Funding Information:
The authors wish to thank Drs. Jolie Schafer, Arianexys Aquino Lopez, and Anitha Somanchi for aid in experimental techniques. Funding. This work was supported by the Schissler Foundation Fellowship (to CB), the Center for Cancer Epigenetics Scholar Award (to CB and MF) and from the (i) National Institutes of Health: R21 NS093387 (to JC); R61 NS111058 (to JC) and the (ii) Brain Tumor SPORE: P50 CA127001 (Developmental Research Project to JC).
Publisher Copyright:
© Copyright © 2020 Bailey, Figueroa, Gangadharan, Lee and Chandra.
PY - 2020/9/17
Y1 - 2020/9/17
N2 - Cell therapies such as chimeric-antigen receptor (CAR) T-cells and NK cells are cutting-edge methods for treating cancer and other diseases. There is high interest in optimizing drug treatment regimens to best work together with emerging cell therapies, such as targeting epigenetic enzymes to stimulate recognition of tumor cells by immune cells. Herein, we uncover new mechanisms of the histone demethylase LSD1, and various inhibitors targeting unique domains of LSD1, in the function of NK cells grown for cell therapy. Catalytic inhibitors (tranylcypromine and the structural derivatives GSK LSD1 and RN-1) can irreversibly block the demethylase activity of LSD1, while scaffolding inhibitors (SP-2509 and clinical successor SP-2577, also known as seclidemstat) disrupt epigenetic complexes that include LSD1. Relevant combinations of LSD1 inhibitors with cell therapy infusions and immune checkpoint blockade have shown efficacy in pre-clinical solid tumor models, reinforcing a need to understand how these drugs would impact T- and NK cells. We find that scaffolding LSD1 inhibitors potently reduce oxidative phosphorylation and glycolysis of NK cells, and higher doses induce mitochondrial reactive oxygen species and depletion of the antioxidant glutathione. These effects are unique to scaffolding inhibitors compared to catalytic, to NK cells compared to T-cells, and importantly, can fully ablate the lytic capacity of NK cells. Supplementation with biologically achievable levels of glutathione rescues NK cell cytolytic function but not NK cell metabolism. Our results suggest glutathione supplementation may reverse NK cell activity suppression in patients treated with seclidemstat.
AB - Cell therapies such as chimeric-antigen receptor (CAR) T-cells and NK cells are cutting-edge methods for treating cancer and other diseases. There is high interest in optimizing drug treatment regimens to best work together with emerging cell therapies, such as targeting epigenetic enzymes to stimulate recognition of tumor cells by immune cells. Herein, we uncover new mechanisms of the histone demethylase LSD1, and various inhibitors targeting unique domains of LSD1, in the function of NK cells grown for cell therapy. Catalytic inhibitors (tranylcypromine and the structural derivatives GSK LSD1 and RN-1) can irreversibly block the demethylase activity of LSD1, while scaffolding inhibitors (SP-2509 and clinical successor SP-2577, also known as seclidemstat) disrupt epigenetic complexes that include LSD1. Relevant combinations of LSD1 inhibitors with cell therapy infusions and immune checkpoint blockade have shown efficacy in pre-clinical solid tumor models, reinforcing a need to understand how these drugs would impact T- and NK cells. We find that scaffolding LSD1 inhibitors potently reduce oxidative phosphorylation and glycolysis of NK cells, and higher doses induce mitochondrial reactive oxygen species and depletion of the antioxidant glutathione. These effects are unique to scaffolding inhibitors compared to catalytic, to NK cells compared to T-cells, and importantly, can fully ablate the lytic capacity of NK cells. Supplementation with biologically achievable levels of glutathione rescues NK cell cytolytic function but not NK cell metabolism. Our results suggest glutathione supplementation may reverse NK cell activity suppression in patients treated with seclidemstat.
KW - LSD1
KW - NK cell
KW - antioxidant
KW - glutathione
KW - metabolism
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UR - http://www.scopus.com/inward/citedby.url?scp=85091955584&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.02196
DO - 10.3389/fimmu.2020.02196
M3 - Article
C2 - 33042135
AN - SCOPUS:85091955584
SN - 1664-3224
VL - 11
JO - Frontiers in immunology
JF - Frontiers in immunology
M1 - 2196
ER -