ICOSL expressed in triple-negative breast cancer can induce Foxp3+Treg cell differentiation and reverse p38 pathway activation

Inducible costimulator ligand (ICOSL) expressed on cancer cells has immunoregulatory functions in vari-ous malignancies. However, the role of ICOSL in triple-negative breast cancer (TNBC) remains unclear. In this study, the role and expression of ICOSL in TNBC were analyzed using the cBioPortal and GEPIA databases. Then the role of ICOSL in Foxp3+ Treg cell differentiation, reversal of p38 pathway activation and cell proliferation, migration and apoptosis was determined in vitro. Finally, the effect of ICOSL expression on TNBC progression was verified in a nude mouse model of TNBC. We here observed that ICOSL expression in TNBC was found to be related to relapse-free survival, and Treg abundance was positively correlated with ICOSL expression, as demonstrated by database analyses. In vitro experiments showed that ICOSL overexpression (OE) in MDA-MB-231 cells induced cocultured T cells to differentiate into Foxp3+ Treg cells and promoted secretion of the tumor-promoting factors IL-10 and IL-4. Furthermore, in vitro experiments showed that ICOSL reversed p38 phosphorylation and promoted the proliferation, invasion, and metastasis of MDA-MB-231 ICOSL-OE cells. Finally, tumor progression was found to be promoted by ICOSL expression in a TNBC nude mouse model. Together, ICOSL expression can enhance tumor cell growth by inducing Foxp3+ Treg cell differentiation and reversing p38 pathway activation in TNBC.

Automated summary

This study revealed that ICOSL expression is associated with relapse-free survival in TNBC and positively correlated with Treg abundance. Overexpression of ICOSL induced T cell differentiation into Foxp3+ Treg cells and promoted secretion of tumor-promoting factors. Additionally, ICOSL expression reversed p38 pathway activation and enhanced proliferation, invasion, and metastasis of TNBC cells.