Abstract
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.
Highlights
In chronic viral infections such as HIV, HCV and cancer, T cells receive persistent molecular signals from antigens or inflammation
We found that Staphylococcal Enterotoxin B (SEB) stimulation of peripheral blood mononuclear cells (PBMCs) for 72hrs in the presence of α-PD-1, CTLA-4 or PD-L1 antibodies led to a significant increase in IL-2 production (Figure 1A, 1B)
We consistently found that CD4+ and CD8+ T cells stimulated with α-CD3/CD28 in the presence of atorvastatin exhibited significant reduction in the expression of PD-1, LAG-3, CD160, TIM-3, CTLA4 and 2B4 (CD244) in a dose-dependent manner after 48 and 72hrs (Figure 2A, 2B and Supplementary Figure 2A)
Summary
In chronic viral infections such as HIV, HCV and cancer, T cells receive persistent molecular signals from antigens or inflammation. This induces a state of dysfunctionality in T cells termed T cell exhaustion [1]. Exhausted T cells lose their robust effector functions such as the ability to produce cytokines, proliferative capacity, and eventually the ability to kill virus-infected cells and tumor cells. Instead they over-express multiple co-inhibitory receptors (immune checkpoints) [1, 2]. Recent advances in the field have demonstrated that T cell exhaustion www.impactjournals.com/oncotarget is reversible in several type of cancers and this has attracted significant attention as a novel game-changing immunotherapy strategy [7,8,9]
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