Figure 2.

Functional dynamics of tT_reg and pT_reg in cancer. This picture summarizes development, heterogeneity, plasticity, antigen specificity, and function of pT_reg and tT_reg in cancer. Activated T_reg, which are epigenetically committed and mostly self- and TAA-specific, can transiently lose Foxp3 without methylating TSDR thus becoming latent T_reg; in some conditions, they can acquire T-bet expression thus becoming specialized suppressors, detrimental to the anti-tumor type-1 response. Activated T_conv, mostly foreign (TSA) antigen-specific, can promiscuously express Foxp3 without demethylating TSDR. However, a fraction (CD25⁺, or CD39⁺) of activated T_conv can convert into pT_reg, progressively moving from an uncommitted to a committed stage. Through IL-10, committed pT_reg can suppress pro-tumoral inflammatory and type-17 responses, thus exerting beneficial roles for the host in some cancer types. In some contexts, uncommitted pT_reg (and possibly activated T_conv) can move back to exT_reg stage, acquiring the ability to produce inflammatory cytokines. Therefore, in some tumors such as colon cancer, Th17-like T_reg may foster type-17 inflammation thus supporting tumor growth; in other tumor contexts, Th1-like T_reg can favor type-1 responses that rather block tumor growth. Green, cells specific for self-antigens and TAA; light blue, cells specific for foreign antigens including TSA. Yellow dash, demethylated TSDR; blue dash, methylated TSDR. Red “F” in yellow circles, stable Foxp3; yellow “F” in empty circles, unstable Foxp3. Dashed arrows, unclear events. Orange rounded arrows, proliferation in the tT_reg or the pT_reg homeostatic niche. Light green frames, conditions in which T_reg are beneficial to the host; light orange frames, conditions in which T_reg are detrimental to the host.