Convergences and Divergences of Thymus- and Peripherally Derived Regulatory T Cells in Cancer

The expansion of regulatory T cells (T(reg)) is a common event characterizing the vast majority of human and experimental tumors and it is now well established that T(reg) represent a crucial hurdle for a successful immunotherapy. T(reg) are currently classified, according to their origin, into thymus-derived T(reg) (tT(reg)) or peripherally induced T(reg) (pT(reg)) cells. Controversy exists over the prevalent mechanism accounting for T(reg) expansion in tumors, since both tT(reg) proliferation and de novo pT(reg) differentiation may occur. Since tT(reg) and pT(reg) are believed as preferentially self-specific or broadly directed to non-self and tumor-specific antigens, respectively, the balance between tT(reg) and pT(reg) accumulation may impact on the repertoire of antigen specificities recognized by T(reg) in tumors. The prevalence of tT(reg) or pT(reg) may also affect the outcome of immunotherapies based on tumor-antigen vaccination or T(reg) depletion. The mechanisms dictating pT(reg) induction or tT(reg) expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape. Indeed, selected T(reg) subsets may display peculiar characteristics in terms of stability, suppressive function, and cytokine production, depending on microenvironmental signals. These features may be differentially distributed between pT(reg) and tT(reg) and may significantly affect the possibility of manipulating T(reg) in cancer therapy. We propose here that innovative immunotherapeutic strategies may be directed at diverting unstable/uncommitted T(reg), mostly enriched in the pT(reg) pool, into tumor-specific effectors, while preserving systemic immune tolerance ensured by self-specific tT(reg).