Thymic stromal lymphopoietin (TSLP) receptor signaling controls a tumorigenic Treg to promote colorectal cancer

Abstract

Abstract Regulatory T cell (Treg) is a hallmark of progression of cancer. However, the subset of Tregs and the factor regulating Tregs in colorectal cancers (CRCs) have not been defined. We identified a novel subset of Tregs expressing TSLP receptor (TSLPR) and ST2 was predominantly associated with CRC in human and mouse. Mef2c, a transcription factor, exclusively expressed on this Treg controlled the expression of CTLA-4 on this Treg under TSLPR signaling. To study the role of TSLP signaling on this Treg, we examined mice lacking TSLPR on Tregs (TSLPRΔTreg) in AOM/DSS-induced CRC model. The results showed that the number and the expression of CTLA-4 on this Treg were lower in TSLPRΔTreg mice and the size and number of tumors were reduced compared to control mice, concomitant with increase of Th1 cells. In addition, in human CRCs, the number of TSLPR+ ST2+ Tregs is negatively correlated with the number of Th1 cells. These findings suggested that TSLPR+ ST2+ Tregs play a pivotal role in progression of CRC through suppression of anti-tumor immunity in CRCs in human and mouse. Furthermore, to address the cure of CRC, we administrated mice with neutralization antibody for TSLP after development of colorectal tumors. Blockage of TSLP signaling reduced size and number of tumors via reduction of TSLPR+ ST2+ Tregs, indicating that neutralization of TSLP inhibits progression of CRCs. Taken together, and TSLP signaling on tumorigenic TSLPR+ ST2+ Treg can be good therapeutic targets for CRC.