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

Burocchi A, Colombo MP, Piconese S - Front Immunol (2013)

Bottom Line: The mechanisms dictating pTreg induction or tTreg expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology Unit, Department of Experimental Medicine, Fondazione IRCCS "Istituto Nazionale Tumori," Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus

Functional dynamics of tTreg and pTreg in cancer. This picture summarizes development, heterogeneity, plasticity, antigen specificity, and function of pTreg and tTreg in cancer. Activated Treg, which are epigenetically committed and mostly self- and TAA-specific, can transiently lose Foxp3 without methylating TSDR thus becoming latent Treg; in some conditions, they can acquire T-bet expression thus becoming specialized suppressors, detrimental to the anti-tumor type-1 response. Activated Tconv, mostly foreign (TSA) antigen-specific, can promiscuously express Foxp3 without demethylating TSDR. However, a fraction (CD25+, or CD39+) of activated Tconv can convert into pTreg, progressively moving from an uncommitted to a committed stage. Through IL-10, committed pTreg can suppress pro-tumoral inflammatory and type-17 responses, thus exerting beneficial roles for the host in some cancer types. In some contexts, uncommitted pTreg (and possibly activated Tconv) can move back to exTreg stage, acquiring the ability to produce inflammatory cytokines. Therefore, in some tumors such as colon cancer, Th17-like Treg may foster type-17 inflammation thus supporting tumor growth; in other tumor contexts, Th1-like Treg 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 tTreg or the pTreg homeostatic niche. Light green frames, conditions in which Treg are beneficial to the host; light orange frames, conditions in which Treg are detrimental to the host.
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Figure 2: Functional dynamics of tTreg and pTreg in cancer. This picture summarizes development, heterogeneity, plasticity, antigen specificity, and function of pTreg and tTreg in cancer. Activated Treg, which are epigenetically committed and mostly self- and TAA-specific, can transiently lose Foxp3 without methylating TSDR thus becoming latent Treg; in some conditions, they can acquire T-bet expression thus becoming specialized suppressors, detrimental to the anti-tumor type-1 response. Activated Tconv, mostly foreign (TSA) antigen-specific, can promiscuously express Foxp3 without demethylating TSDR. However, a fraction (CD25+, or CD39+) of activated Tconv can convert into pTreg, progressively moving from an uncommitted to a committed stage. Through IL-10, committed pTreg can suppress pro-tumoral inflammatory and type-17 responses, thus exerting beneficial roles for the host in some cancer types. In some contexts, uncommitted pTreg (and possibly activated Tconv) can move back to exTreg stage, acquiring the ability to produce inflammatory cytokines. Therefore, in some tumors such as colon cancer, Th17-like Treg may foster type-17 inflammation thus supporting tumor growth; in other tumor contexts, Th1-like Treg 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 tTreg or the pTreg homeostatic niche. Light green frames, conditions in which Treg are beneficial to the host; light orange frames, conditions in which Treg are detrimental to the host.

Mentions: During the latest years, it has become increasingly clear that Treg, meant as Foxp3-positive cells, are not a homogeneous lineage, but rather represent a mixture of subpopulations. Indeed, beside the tTreg/pTreg distinction based on their developmental origin, diverse Treg subsets can be identified endowed with peculiar features in terms of suppression, proliferation, and stability, even though not properly classifiable as developmentally distinct lineages (Figure 2). Tumor microenvironmental signals may differentially affect these subsets, thus shaping Treg heterogeneity to the advantage of tumor progression.


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

Burocchi A, Colombo MP, Piconese S - Front Immunol (2013)

Functional dynamics of tTreg and pTreg in cancer. This picture summarizes development, heterogeneity, plasticity, antigen specificity, and function of pTreg and tTreg in cancer. Activated Treg, which are epigenetically committed and mostly self- and TAA-specific, can transiently lose Foxp3 without methylating TSDR thus becoming latent Treg; in some conditions, they can acquire T-bet expression thus becoming specialized suppressors, detrimental to the anti-tumor type-1 response. Activated Tconv, mostly foreign (TSA) antigen-specific, can promiscuously express Foxp3 without demethylating TSDR. However, a fraction (CD25+, or CD39+) of activated Tconv can convert into pTreg, progressively moving from an uncommitted to a committed stage. Through IL-10, committed pTreg can suppress pro-tumoral inflammatory and type-17 responses, thus exerting beneficial roles for the host in some cancer types. In some contexts, uncommitted pTreg (and possibly activated Tconv) can move back to exTreg stage, acquiring the ability to produce inflammatory cytokines. Therefore, in some tumors such as colon cancer, Th17-like Treg may foster type-17 inflammation thus supporting tumor growth; in other tumor contexts, Th1-like Treg 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 tTreg or the pTreg homeostatic niche. Light green frames, conditions in which Treg are beneficial to the host; light orange frames, conditions in which Treg are detrimental to the host.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3753661&req=5

Figure 2: Functional dynamics of tTreg and pTreg in cancer. This picture summarizes development, heterogeneity, plasticity, antigen specificity, and function of pTreg and tTreg in cancer. Activated Treg, which are epigenetically committed and mostly self- and TAA-specific, can transiently lose Foxp3 without methylating TSDR thus becoming latent Treg; in some conditions, they can acquire T-bet expression thus becoming specialized suppressors, detrimental to the anti-tumor type-1 response. Activated Tconv, mostly foreign (TSA) antigen-specific, can promiscuously express Foxp3 without demethylating TSDR. However, a fraction (CD25+, or CD39+) of activated Tconv can convert into pTreg, progressively moving from an uncommitted to a committed stage. Through IL-10, committed pTreg can suppress pro-tumoral inflammatory and type-17 responses, thus exerting beneficial roles for the host in some cancer types. In some contexts, uncommitted pTreg (and possibly activated Tconv) can move back to exTreg stage, acquiring the ability to produce inflammatory cytokines. Therefore, in some tumors such as colon cancer, Th17-like Treg may foster type-17 inflammation thus supporting tumor growth; in other tumor contexts, Th1-like Treg 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 tTreg or the pTreg homeostatic niche. Light green frames, conditions in which Treg are beneficial to the host; light orange frames, conditions in which Treg are detrimental to the host.
Mentions: During the latest years, it has become increasingly clear that Treg, meant as Foxp3-positive cells, are not a homogeneous lineage, but rather represent a mixture of subpopulations. Indeed, beside the tTreg/pTreg distinction based on their developmental origin, diverse Treg subsets can be identified endowed with peculiar features in terms of suppression, proliferation, and stability, even though not properly classifiable as developmentally distinct lineages (Figure 2). Tumor microenvironmental signals may differentially affect these subsets, thus shaping Treg heterogeneity to the advantage of tumor progression.

Bottom Line: The mechanisms dictating pTreg induction or tTreg expansion/stability are a matter of intense investigation and the most recent results depict a complex landscape.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.

View Article: PubMed Central - PubMed

Affiliation: Molecular Immunology Unit, Department of Experimental Medicine, Fondazione IRCCS "Istituto Nazionale Tumori," Milan , Italy.

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.

No MeSH data available.


Related in: MedlinePlus