Suppression of IFN-γ expression in Treg cells is dependent on the TCR signaling pathway 2137

Abstract Description Regulatory T cells (Treg) play a key role in immune homeostasis by suppressing excessive immune responses. Treg’s presence in tumors is usually correlated with poor cancer prognosis as it suppresses anti-tumor immune responses. Unlike in effector T cells, the expression of IFN-γ, one of the major cytokines that promote anti-tumor immune response, is suppressed in Treg. The detailed molecular mechanism of this suppression remains unclear. The induction of IFN-γ in Treg will not only tame Treg’s immune suppressive function but also switch Treg into a more pro-inflammatory state to further enhance tumor elimination. Here, we performed a genome-wide CRISPR/Cas9-based screen to identify genes that are involved in the suppression of IFN-γ expression in Tregs. One of the candidate genes from the screen was ZAP70, a component of the TCR signaling pathway. The ablation of ZAP70 and other genes in the TCR pathway led to a significant increase in IFN-γ expression in Tregs while maintaining Foxp3 expression level. Using an adoptive T cell transfer tumor model, we observed a reduction in tumor size in mice transferred with ZAP70-deficient Tregs. Our results suggested that the TCR signaling components in Treg could be potential targets for enhancing anti-tumor immune response. Funding Sources R01-AI1511123 Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)