Human Pancreatic Carcinoma-Associated Fibroblasts Promote Expression of Co-inhibitory Markers on CD4+ and CD8+ T-Cells

Discussion Tumors have developed several strategies to escape anti-tumor immunity, including physical barriers and recruitment of immunosuppressive cells. In pancreatic cancer, the tumor microenvironment is dominated by a dense stroma created by activated CAFs, which mediate tumor growth and progression by producing extracellular matrix proteins, growth factors, chemokines, and cytokines. Numerous studies have explored the immunosuppressive properties of CAFs and their role in supporting tumor cell growth by favoring the presence of tumor promoting immune cells [reviewed in Ziani et al. (29)]. However, most studies have focused on the effect of CAFs on the innate immune cells, rather than on the adaptive immune response. Since T-cells are the dominant immune cell subset with a potential capacity to eradicate tumor cells, we have performed an in-depth examination of how CAFs affect the phenotype and activation status of T-cells. One of the most interesting findings was that CAFs induce the expression of the co-inhibitory markers TIM-3, PD-1, CTLA-4, and LAG-3 on activated T-cells upon stimulation. We further identified PGE2 as an inducer of co-inhibitory marker expression. In addition, T-cells expressing immune checkpoints produce less IFN-γ, TNF-α, and CD107a after restimulation when CAFs had been present, suggesting that CAPCSs promote T-cell exhaustion that leads to functional incapacity. We used OKT3 as a stimulation since it is commonly used to study T ce...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research