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T-regulatory cells are an upsurge in the tumor microenvironment and induce immune-evasion. CD4 +  Treg cells are well characterized whereas the role of CD8 +  Tregs in cancer has recently started to crease attention. Here, we report an augmentation CD8 + FOXP3 +  Tregs in breast tumor microenvironment. FOXP3, the lineage-specific transcription factor, is a dominant regulator of Treg cell development and function. FOXP3 is induced preferentially by divergent signaling in CD4 +  Treg cells. But how  FOXP3  is induced and maintained in tumor-CD8 +  Tregs is the Cinderella of the investigation. We observed that RUNX3, a CD8 +  lineage-specific transcription factor, binds at the  FOXP3 -promoter to induce its transcription. In addition to promoter activation, involvement of  cis -elements CNS1 and CNS2 in the transcriptional regulation of  FOXP3  was also evident in these cells. SMAD3 binds to CNS1 region and acts as transcription inducer, whereas GATA3 plays a temporal role in the  FOXP3  transcription by differential chromatin modification in CNS regions. In CNS1 region, GATA3 acts as a repressor for  FOXP3  in naïve CD8 +  T cells. Whereas in CD8 +  Tregs, GATA3 binds directly at CNS2 region and persuaded the maintenance of  FOXP3 . Therefore, the intervention of these concerted transcriptional machinery may have a therapeutic potential in immunotherapy of cancer.

Transcriptional regulation of FOXP3 requires integrated activation of both promoter and CNS regions in tumor-induced CD8+ Treg cells