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

Abstract

The expansion of regulatory T cells (Treg) is a common event characterizing the vast majority of human and experimental tumors and it is now well established that Treg represent a crucial hurdle for a successful immunotherapy. Treg are currently classified, according to their origin, into thymus-derived Treg (tTreg) or peripherally induced Treg (pTreg) cells. Controversy exists over the prevalent mechanism accounting for Treg expansion in tumors, since both tTreg proliferation and de novo pTreg differentiation may occur. Since tTreg and pTreg are believed as preferentially self-specific or broadly directed to non-self and tumor-specific antigens, respectively, the balance between tTreg and pTreg accumulation may impact on the repertoire of antigen specificities recognized by Treg in tumors. The prevalence of tTreg or pTreg may also affect the outcome of immunotherapies based on tumor-antigen vaccination or Treg depletion. The mechanisms dictating pTreg induction or tTreg expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape. Indeed, selected Treg 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 pTreg and tTreg and may significantly affect the possibility of manipulating Treg 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 tTreg.

Keywords: Treg development; epigenetic commitment; heterogeneity; plasticity; specialization; tumor antigens.

Figure 1

T_reg suppressive mechanisms in tumor microenvironment. T_reg use different strategies to inhibit target cells within the tumor mass. Three types of T_reg-related molecules can mediate these suppressive mechanisms: (1) surface molecules (upper panel); (2) enzymes (middle panel), and (3) cytokines (lower panel). (1) Among the surface molecules expressed by T_reg, CTLA-4, LAG-3, Nrp-1, and RANKL have a well-demonstrated role in promoting tumor progression, mainly modulating DC activation and function. In particular CTLA-4 and LAG-3, binding to CD80/CD86 (B7-1/2), and MHCII respectively, significantly impair DC capacity to activate T_conv. In addition CTLA-4 promotes IDO expression and the production of the pro-apoptotic metabolite kynurenine. Nrp-1 instead stabilizes T_reg-DC contact, allowing T_reg to adequately suppress DC. Although the course of action of RANKL is not yet well defined, its expression is associated to tumor metastatization. (2) The two ecto-enzymes CD39 and CD73 generate from ATP pericellular adenosine, which is endowed with strong tolerogenic effects. Also cAMP, similarly to adenosine, interferes with T_conv activation and survival. Granzyme and perforin induce the apoptosis of target cells by cytolysis. (3) T_reg secrete several immune-modulatory cytokines, which could directly modulate T_conv functions (TGF-β, IL-10, and IL-35), or indirectly promote the establishment of pro-tumorigenic microenvironment (VEGF).

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.