TLR Stimulation of Antigen-Presenting Cells Leads to IL-12 Expression that Decreases PD-1 Expression on Activated CD8+ T-Cells

Identification: Zahm, Christopher


Description

TLR Stimulation of Antigen-Presenting Cells Leads to IL-12 Expression that Decreases
PD-1 Expression on Activated CD8+ T-Cells
 
Christopher D. Zahm1, Viswa T. Colluru1, Sean J. McIlwain1,2, Irene M. Ong1,2,3, Douglas G. McNeel1*
1University of Wisconsin Carbone Cancer Center; 2Department of Biostatistics and Medical Informatics; 3Department of Obstetrics and Gynecology, University of Wisconsin, Madison, WI 53705
 
Expression of T-cell checkpoint molecules, and their ligation by ligands present in the tumor microenvironment, can severely compromise anti-tumor immunity. Blockade of these receptors, notably PD-1 and LAG-3, both in exhausted T cells, and at the time of T-cell activation with vaccination, can improve anti-tumor immunity. We evaluated whether T-cell checkpoint molecule expression could be separated from T-cell activation in the context of innate immune stimulation with TLR agonists. We found that ligands for TLR1/2, TLR7, and TLR9 led to a specific decrease in expression of PD-1 on antigen-activated naïve T-cells. These effects were mediated by IL-12 released by professional antigen-presenting cells. Gene expression analysis demonstrated that T cells activated in the presence of either TLR1/2 or TLR7 agonists had similar transcriptional profiles associated with increased effector function. In two separate tumor models, treatment with anti-tumor vaccines in the presence of TLR1/2 or TLR7 ligands induced antigen-specific CD8+ T cells with lower PD-1 expression and improved anti-tumor immunity. These findings underscore the importance of innate immune activation in the development of CD8+ effector T cells, and suggest specific TLR agonists can be strategically used to modulate the expression of specific T-cell checkpoint molecules at the time of T-cell activation.
 
 
 

Credits

Credits: None available.

You must be logged in and own this product in order to post comments.