Cholesterol Esterification Enzyme Inhibition Enhances Antitumor Effects of Human Chimeric Antigen Receptors Modified T Cells

Abstract

Chimeric antigen receptor-modified T cell (CART) therapy has been demonstrated to have significant effect on hematologic tumor in patients. However, many persistent obstacles and challenges still limit the application. It is known that CD8 T cells are a key component of antitumor immunity. An avasimibe-induced inhibition of cholesterol esterification has been shown to improve the antitumor response of CD8 T cells in mice. In this study, using human CD19-directed CART cells as effector cells and CD19-overexpressing K562 cells as target cells, we detected whether cholesterol acyltransferase inhibition by avasimibe can enhance the antitumor effect of human CART cells. After avasimibe treatment, the infection rate was dropped by up to 50% (P<0.05). The cytotoxic effect of CART cells was significantly increased than the control group in a dose-dependent manner. Moreover, the level of secreted interferon-γ increased in almost half of the cases (P<0.05); the ratio of CD8CD4 T cells was increased among the total T cells and the CART cells in some of cases (P<0.05). Our study suggests that inhibition of cholesterol acyltransferase can promote the antitumor effect of CART cells, and provides a new option for a combination therapy by regulating T-cell metabolism to enhance antitumor effects.

Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

“…CE accumulation might be related to the upregulation of caveolin-1, which promotes the gemcitabine-resistance. Furthermore, it is worth noting that a few recent studies have reported an enhanced antitumor activity of immune system when cholesterol esterification is blocked [ 31 , 32 ]. ACAT1 inhibitors was shown to increase plasma membrane cholesterol level and promote proliferation of CD8 + T cells [ 32 ].…”

“…ACAT1 inhibitors was shown to increase plasma membrane cholesterol level and promote proliferation of CD8 + T cells [ 32 ]. Combination of avasimibe with immunotherapy, such as anti-PD-1 antibody therapy or chimeric antigen receptor-modified T cell therapy, show enhanced antitumor effects [ 31 , 32 ]. These results suggest that immune response plays an important role in avasimibe’s antitumor effects, and possibly in overcoming gemcitabine resistance in pancreatic cancers.…”

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

“…In addition to having direct effects on cancer cells, CE inhibition affects human chimeric antigen receptor-modified T cells. Administration of avasimibe augments the in vitro cytotoxic effect of these cells, an effect that can be partly explained by an increased ratio of cytotoxic CD8 T cells 114 . This observation is consistent with findings showing that avasimibe treatment effectively promotes CD8 effector T cell function 87,115 .…”

Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator

“…TCR signal transduction is influenced by lipid metabolism, in part because non-esterified cholesterol is a major component of lipid rafts which localize TCR to sites of antigen presentation [ 10 , 11 ]. Acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) is the dominant enzyme in CD8 + T cells that converts free cholesterol to cholesteryl esters and attenuates lipid raft formation [12] . ACAT1 deficiency leads to higher plasma membrane cholesterol levels in CD8 + T cells, and this correlates with higher TCR signaling levels after stimulation [13] .…”