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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 .

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