Wednesday, March 23, 2016

Availability of free cytoplasmic cholesterol augments TCR signaling in CD8 T cells

This study focus on Acat1 that encodes cholesterol esterification enzymes that convert free cholesterol to cholesteryl esters for storage. The scientists noticed that chemical inhibition of Acat1 in CD8 T cells could augment their cytolytic effector differentiation (granzyme B ↑).

Similar results were obtained with CD8 T cells from Acat1 conditional knockout mice (Acat1CKO).

Boost of CD8 T cell cytolytic functions with Acat1 inactivation yielded better tumor protection in adoptive transfer experiments as well.

Mechanistically, it appears that availability of excess free cholesterol in Acat1CKO CD8 T cells improved TCR downstream signaling.

Finally, the authors showed that avasimibe, an Acat inhibitor with a good safety profile in humans, could delay tumor progression in mice and even show synergy with checkpoint inhibitor, anti-PD1 antibody.

In summary, this study suggests that commonly used cholesterol modulating drugs could have important role in CD8 T cells effector function and could influence tumor immunotherapy results.

Here I would like to note that one earlier study showed that reduction of cellular free cholesterol triggered universal STING-cGAS mediated anti-viral type I IFN response. This suggests that on one hand free cholesterol could augment CD8 T cell cytolytic function, but on the other hand it could diminish cell-autonomous anti-viral response.  

David Usharauli

No comments:

Post a Comment