Convergences and divergences of tnymus- and peripherally derived regulatory T cells in cancer

The expansion of regulatoryT 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 (T-reg) or peripherally induced T-reg (pT(reg)) cells. Controversy exists over the prevalent mechanism accounting for T-reg expansion in tumors, since both tIreg proliferation and de novo pIreg differentiation may occur. Since tIreg and pIreg are believed as preferentially self-specific or broadly directed to non-self and tumor-specific antigens, respectively, the balance between tT(reg) and pIreg 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 pIreg 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 tIreg.