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Modulating cholesterol metabolism boosts tumour response

by ecancer reporter Janet Fricker

Modifying cholesterol metabolism may offer a new approach to increase the anti cancer activity of CD8 T cells (also known as killer T cells), report Chinese investigators in Nature.

While CD8 T cells provide tumour surveillance and have direct antitumour effects, tumours are able to escape T-cell attack through a variety of mechanisms operating in the tumour microenvironment.

Since cholesterol is a component of membrane lipids, which are key regulators of T-cell signalling, Chenqi Xu and colleagues, from the Chinese Academy of Sciences, Shanghai, investigated whether anti tumour responses might be potentiated through modifying cholesterol metabolism.

The team genetically modified mice so that their T cells lacked the cholesterol esterification enzyme acetyl-CoA acetyltransferase 1 (ACAT1).

The loss of ACAT1, they found, resulted in an increase in the anti tumour activity of CD8 cells.

Next, the investigators showed avasimibe, a small molecule inhibitor of ACAT1, displayed good anti tumour effects in mouse tumour models of melanoma and lung cancer.

Finally, when avasimibe was combined with a checkpoint blockade drug (the anti-PD-1 antibody), they showed anti-tumour effects were further enhanced.

“ACAT1 inhibition can be used to complement current therapies such as immune checkpoint blockade because it acts through a different mechanism,” wrote the authors.

In an accompanying ‘News & Views’ article Michael Dustin, from the University of Oxford, wrote, “Many people with cancer fail to respond to checkpoint-blockade drugs, so there is still room for improvement of this breakthrough therapy.

“Therefore, it is exciting to speculate that Yang and colleagues’ basic observations and preclinical data might be a first step towards a pill for boosting killer T cells as part of anticancer and antiviral therapies.”

References

Yang W, Bai Y, Xiong Y, et al. Potentiating the antitumour response of CD8 T cells by modulating cholesterol metabolism. Nature, 16 March 2016

Dustin A. Killers on sterols. News & Views. Nature, 16 March 2016


 

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