The T cell receptor (TCR) repertoire of circulating TReg II cells parallels that of intratumoral TReg cells. Thus, it is hypothesized that TReg II cells could be primed through primary exposure to the cancer cells and/or antigen-presenting cells (APCs) within the tumor microenvironment (TME), and tumor-derived TReg II cells then enter the circulation after being ‘educated’ in the TME and/or tumor-involved draining lymph nodes. Given the continued expression of CCR8 by the circulating immunosuppressive TReg II cells, these specific TReg cells could then be recruited to cancer cells seeded at distant metastatic sites and may play an important role in propagating a systemic immune-suppressive microenvironment. Abbreviations: CTL, cytotoxic T lymphocyte; IDO, indoleamine 2,3-dioxygenase; IL-6, interleukin 6; MDSC, myeloid-derived suppressor cell; PGE2, prostaglandin E2; Th cell, T helper cell.