Journal
ONCOTARGET
Volume 8, Issue 58, Pages 98215-98232Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.21003
Keywords
inhibitory receptors; atorvastatin; immune checkpoints
Categories
Funding
- Canadian Institutes of Health Research (CIHR)
- CIHR
Ask authors/readers for more resources
Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy-resulting in restoration of T cell function and reduction of viral load or tumour growth. Immunomodulatory roles of commonly used cholesterol-lowering medications, atorvastatin and other statins, are widely documented. We have previously shown that atorvastatin can inhibit HIV-1 infection and replication. Here, for the very first time we discovered that atorvastatin also regulates activated T cell function by mediating downregulation of multiple co-inhibitory receptors, which corresponded with increased IL-2 production by stimulated T cells. In addition, we found that atorvastatin treatment reduces expression of mTOR and downstream T cell effector genes. We demonstrate a novel mechanism showing that atorvastatin inhibition of Ras-activated MAPK and PI3K-Akt pathways, and subsequent mTOR signalling promotes gross downregulation of co-inhibitory receptors. Thus, our results suggest that statins may hold particular promise in reinvigorating T cell function in chronic conditions.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available