Analysis of the T-Cell Receptor Repertoires of Tumor-Infiltrating Conventional and Regulatory T Cells Reveals No Evidence for Conversion in Carcinogen-Induced Tumors

Hindley, James P.; Ferreira, Cristina; Jones, Emma; Lauder, Sarah N.; Ladell, Kristin; Wynn, Katherine K.; Betts, Gareth J.; Singh, Yogesh; Price, David A.; Godkin, Andrew; Dyson, Julian; Gallimore, Awen

doi:10.1158/0008-5472.can-10-1797

Cited by 107 publications

(103 citation statements)

References 38 publications

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“…The hypothesis of the authors of this study was that if Tregs in the tumor truly derived from conventional CD4 + T cells, then the overlap between the TCR repertoire of these two cell subsets would have been higher. Thus, they concluded that TITregs originated from nTregs [62]. In another study, the immunoscope technology was employed to analyze the TCR repertoire of CD4 + TILs in mice bearing TC-1 solid neoplasms.…”

Section: Migration and Retention Of Tregsmentioning

confidence: 99%

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tanchot

Terme

Péré

et al. 2012

Cancer Microenvironment

115

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In immunocompetent individuals, the immune system initially eradicates potentially tumorigenic cells as they develop, a capacity that is progressively lost when malignant cells acquire alterations that sustain immunosubversion and/or immunoevasion. One of the major mechanisms whereby cancer cells block antitumor immune responses involves a specific class of immunosuppressive T cells that-in the vast majority of cases-express the Forkhead box P3 (FOXP3) transcription factor. Such FOXP3 + regulatory T cells (Tregs) accumulate within neoplastic lesions as a result of several distinct mechanisms, including increased infiltration, local expansion, survival advantage and in situ development from conventional CD4 + cells.

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Section: Migration and Retention Of Tregsmentioning

confidence: 99%

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tanchot

Terme

Péré

et al. 2012

Cancer Microenvironment

115

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show abstract

“…By expressing high levels of CCR4, nTreg are recruited to CCL22 rich tumor microenvironments. [7][8][9] Here, nTreg actively expand and suppress other immune cells in a cell-contact dependent manner. 3,8 Thus, it is clear that various subpopulations of Tregs endowed with various suppressive functions co-exist in cancer patients.…”

Section: Introductionmentioning

confidence: 99%

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

et al. 2014

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C regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3 C Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8C T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.

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“…Early work suggested that the tumor microenvironment is conducive to both thymic Treg (tTreg) recruitment and generation of peripheral Treg (pTreg) in situ (3)(4)(5)(6). Other reports demonstrated that the preponderance of tTreg versus pTreg is variable and dependent on the tumor type and stage (7)(8)(9). Many of the above studies, however, relied on adoptive transfer of exogenous populations to track thymic versus peripheral Treg in tumors, which complicated interpretation.…”

mentioning

confidence: 99%

Regulatory Rebound in IL-12–Treated Tumors Is Driven by Uncommitted Peripheral Regulatory T Cells

Virtuoso

Anderson

et al. 2015

The Journal of Immunology

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IL-12 promotes a rapid reversal of immune suppression in the tumor microenvironment. However, the adjuvant activity of IL-12 is short-lived due to regulatory T cell (Treg) reinfiltration. Quantitative analysis of Treg kinetics in IL-12–treated tumors and tumor-draining lymph nodes revealed a transient loss followed by a rapid 4-fold expansion of tumor Treg between days 3 and 10. Subset-specific analysis demonstrated that the posttreatment rebound was driven by the CD4+CD25+Foxp3+ neuropilin-1low peripheral Treg (pTreg), resulting in a 3–5-fold increase in the pTreg to CD4+CD25+Foxp3+ neuropilin-1high thymic Treg ratio by day 10. The expanding pTreg displayed hypermethylation of the CpG islands in Treg-specific demethylated region, CTLA-4 exon 2, and glucocorticoid-induced TNFR exon 5, were phenotypically unstable, and exhibited diminished suppressive function consistent with an uncommitted in vitro–induced Treg–like phenotype. In vitro culture of posttherapy Treg populations under Th1-promoting conditions resulted in higher levels of IFN-γ production by pTreg compared with thymic Treg, confirming their transitional state. Blockade of selected molecular mechanisms that are known to promote Treg expansion identified IDO-positive dendritic cells as the primary mediator of post–IL-12 pTreg expansion. Clinical implications of these findings are discussed.

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Analysis of the T-Cell Receptor Repertoires of Tumor-Infiltrating Conventional and Regulatory T Cells Reveals No Evidence for Conversion in Carcinogen-Induced Tumors

Cited by 107 publications

References 38 publications

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Tumor-Infiltrating Regulatory T Cells: Phenotype, Role, Mechanism of Expansion In Situ and Clinical Significance

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

Regulatory Rebound in IL-12–Treated Tumors Is Driven by Uncommitted Peripheral Regulatory T Cells

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