Tgf-β1 produced by activated CD4<sup>+</sup>T Cells Antagonizes T Cell Surveillance of Tumor Development

Donkor, Moses; Sarkar, Anujit; Li, Ming O.

doi:10.4161/onci.1.2.18481

Cited by 50 publications

(31 citation statements)

References 45 publications

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“…TGF-β1 is a multifunctional growth factor that has roles in both promoting and suppressing tumorigenesis 38 . Deleting TGF-β1 specifically from activated CD4 + T cells and Treg cells reduced metastatic B16-OVA tumor cell spread to the mouse lung, indicating that activated CD4 + T-cell-derived TGF-β1 inhibits tumor immunosurveillance 39 . Importantly, we have also shown that FURIN is an important factor in modulating the T helper cell balance.…”

Section: Discussionmentioning

confidence: 66%

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

et al. 2016

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Proprotein convertases (PCSK) have a critical role in the body homeostasis as enzymes responsible for processing precursor proteins into their mature forms. FURIN, the first characterized member of the mammalian PCSK family, is overexpressed in multiple malignancies and the inhibition of its activity has been considered potential cancer treatment. FURIN has also an important function in the adaptive immunity, since its deficiency in T cells causes an impaired peripheral immune tolerance and accelerates immune responses. We addressed whether deleting FURIN from the immune cells would strengthen anticancer responses by subjecting mouse strains lacking FURIN from either T cells or macrophages and granulocytes to the DMBA/TPA two-stage skin carcinogenesis protocol. Unexpectedly, deficiency of FURIN in T cells resulted in enhanced and accelerated development of tumors, whereas FURIN deletion in macrophages and granulocytes had no effect. The epidermises of T-cell-specific FURIN deficient mice were significantly thicker with more proliferating Ki67+ cells. In contrast, there were no differences in the numbers of the T cells. The flow cytometric analyses of T-cell populations in skin draining lymph nodes showed that FURIN T-cell KO mice have an inherent upregulation of early activation marker CD69 as well as more CD4+CD25+Foxp3+ positive T regulatory cells. In the early phase of tumor promotion, T cells from the T-cell-specific FURIN knockout animals produced more interferon gamma, whereas at later stage the production of Th2- and Th17-type cytokines was more prominent than in wild-type controls. In conclusion, while PCSK inhibitors are promising therapeutics in cancer treatment, our results show that inhibiting FURIN specifically in T cells may promote squamous skin cancer development.

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Section: Discussionmentioning

confidence: 66%

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

et al. 2016

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“…In addition, local production of TGFB may further enhance their suppressive activity and may even participate in the conversion of conventional CD4 þ T cells to induced Tregs (iTregs). Of note, several reports have linked TGFB1 to negative regulation of tumor-specific cytotoxic T lymphocyte responses (40)(41)(42)(43)(44). Therefore, upregulation of TGFB production in the colonic mucosa of AOM/DSS-treated P2rx7 À/À mice may also inhibit tumor-specific cytotoxic T cells activity and thereby further participates in tumor promotion.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

et al. 2015

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Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly that while P2RX7 mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFb1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventing CAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result. Cancer Res; 75(5); 835-45. Ó2015 AACR.

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“…Simultaneously, the expression of immunosuppressive cytokines IL-10 and TGF-β1 was dramatically increased with the combined administration of Rapa and imDCs. Although TGF-β1 has been demonstrated to stimulate myofibroblast transdifferentiation, which contributes to matrix deposition that characterizes OB [31], a lot of research has focused on its critical function as an immunosuppressive factor in many diseases [32,33,34]. For heart transplantation, retinoic acid can reduce rejection in a TGF-β-dependent manner by promoting the differentiation of Tregs and inhibiting the differentiation of Th17 cells [33].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

Dong

Wang

Liu

et al. 2015

Int Arch Allergy Immunol

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Background: Obliterative bronchiolitis (OB) ranks as the major obstacle for long-term survival of lung transplantation patients. Rapamycin (Rapa) has recently been confirmed as an immunosuppressant for antirejection due to its suppressive role in T cell activation. Here, we explore the effect of Rapa combined with immature dendritic cells (imDCs) on OB in trachea allograft rats. Methods: The effect of bone marrow-derived imDCs or Rapa-imDCs on lymphocyte cells and CD4⁺ T cells were evaluated by methyl thiazolyl tetrazolium and flow cytometry. Tracheal transplantation was performed from Lewis rats to Wistar recipients. Recipient rats received Rapa+imDCs for 10 consecutive days after implantation. Allograft rejection was assessed by micro-CT image, hematoxylin/eosinHE staining and flow cytometry. The underlying mechanism was also investigated. Results: Rapa-imDCs inhibited lymphocyte and CD4⁺ T cell growth. Furthermore, Rapa-imDC treatment induced T cell hyporesponsiveness by attenuating T cell differentiation into IFN-γ-producing T cells (Th1), but increased CD4⁺CD25⁺Foxp3⁺ T cell (Treg) contents. Importantly, Rapa-imDC administration ameliorated airway obliteration symptoms and CD4⁺ and CD8⁺ T cell infiltration. Furthermore, the proinflammatory factor levels of IL-6, TNF-α, IFN-γ and IL-17 were decreased, concomitant with the upregulation of immunosuppressive cytokines IL-10 and TGF-β1. Further analysis confirmed that Rapa-imDC treatment attenuated the amounts of infiltrated IL-17⁺CD4⁺ T cells (Th17 cells) and Th1 cells, but increased Treg contents in the spleens of recipients. Conclusions: This research may corroborate a protective role of Rapa-imDCs in OB by regulating the balance between effector T cells and Tregs, suggesting a potential applicable strategy to treat OB after lung transplantation.

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Tgf-β1 produced by activated CD4⁺T Cells Antagonizes T Cell Surveillance of Tumor Development

Cited by 50 publications

References 45 publications

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

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Tgf-β1 produced by activated CD4+T Cells Antagonizes T Cell Surveillance of Tumor Development

Cited by 50 publications

References 45 publications

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development

Genetic and Pharmacological Inactivation of the Purinergic P2RX7 Receptor Dampens Inflammation but Increases Tumor Incidence in a Mouse Model of Colitis-Associated Cancer

Rapamycin Combined with Immature Dendritic Cells Attenuates Obliterative Bronchiolitis in Trachea Allograft Rats by Regulating the Balance of Regulatory and Effector T Cells

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Tgf-β1 produced by activated CD4⁺T Cells Antagonizes T Cell Surveillance of Tumor Development