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 ofhuman and experimental tumors and it is now well established that T_reg represent a crucial hurdle fora successful immunotherapy. T_reg are currently classified, according to their origin, into thymus-derived Treg (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 tTreg and pTregaccumulation may impact on the repertoire of antigen specificities recognized by Treg 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 Treg, mostly enriched in the pTreg pool, into tumor-specific effectors, while preserving systemic immune tolerance ensured by self-specific tT_reg.