CD4 + FOXP3Exon2 + regulatory T cell frequency predicts breast cancer prognosis and survival.

CD4 ⁺ FOXP3 ⁺ regulatory T cells (T _regs ) suppress immune responses to tumors, and their accumulation in the tumor microenvironment (TME) correlates with poor clinical outcome in several cancers, including breast cancer (BC). However, the properties of intratumoral T _regs remain largely unknown. Here, we found that a functionally distinct subpopulation of T _regs , expressing the FOXP3 Exon2 splicing variants, is prominent in patients with hormone receptor-positive BC with poor prognosis. Notably, a comprehensive examination of the TCGA validated FOXP3E2 as an independent prognostic marker in all other BC subtypes. We found that FOXP3E2 expression underlies BCs with defective mismatch repair and a stem-like signature and highlights pathways involved in tumor survival. Last, we found that the TME induces FOXP3E2 through the CXCL12/CXCR4 axis and confirmed the higher immunosuppressive capacity of FOXP3E2 ⁺ T _regs derived from patients with BC. Our study suggests that FOXP3E2 ⁺ T _regs might be used as an independent biomarker to predict BC prognosis and survival and to develop super-targeted immunotherapies.