Inhibition of TGF-β1 Signaling Promotes Central Memory T Cell Differentiation

Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne; Tsang, Kwong Y.; Greiner, John W.

doi:10.4049/jimmunol.1300472

Cited by 29 publications

(26 citation statements)

References 31 publications

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“…3). This is in parallel with a recent report showing that blocking endogenous TGF-β1 signaling in CD8 + T cells enhances their conversion into central memory cells 24 . Since FURIN processes pro-TGF-β1, the autocrine TGF-β1 signaling is likely to be defective in FURIN-deficient CD8 + T cells.…”

Section: Resultssupporting

confidence: 86%

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: Resultssupporting

confidence: 86%

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

et al. 2016

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“…Previous findings have suggested that TGF-β inhibits SLEC differentiation and promotes MPEC differentiation during CD8 + effector and memory T-cell development (18)(19)(20). Paradoxically, a recent study has demonstrated that TGF-β inhibits the differentiation of central memory T cells (21), which are derived from MPECs.…”

Section: Resultsmentioning

confidence: 99%

Transforming growth factor-β signaling is constantly shaping memory T-cell population

Zhang

2015

Proc. Natl. Acad. Sci. U.S.A.

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The long-term maintenance of memory T cells is essential for successful vaccines. Both the quantity and the quality of the memory T-cell population must be maintained. The signals that control the maintenance of memory T cells remain incompletely identified. Here we used two genetic models to show that continuous transforming growth factor-β signaling to antigen-specific T cells is required for the differentiation and maintenance of memory CD8 + T cells. In addition, both infection-induced and microbiotainduced inflammation impact the phenotypic and functional identity of memory CD8 + T cells.TGF-β | memory T cell | acute infection | CD8 +

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“…S3E) also fits with this hypothesis as CD25 + CD122 + CD8 + T cells are generally marked for effector differentiation, whereas bonafide central memory CD8 + T cells are generally CD25 − CD122 + (32). TGF-β has been known to suppress formation of memory CD8 + T cells, and tumor derived TGF-β has been proposed to do the same in vivo , resulting in inefficient priming of anti-tumor T cell responses and subpar memory recall responses (33, 34). In our in vitro model system, we were able to demonstrate that FIST15 can expand central memory phenotype CD8 + T cells, although these cells may be destined for further differentiation to effector cells.…”

Section: Discussionmentioning

confidence: 99%

Stimulation of Natural Killer Cell–Mediated Tumor Immunity by an IL15/TGFβ–Neutralizing Fusion Protein

Deng

Chinnadurai

et al. 2016

Cancer Research

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The clinical efficacy of immune cytokines used for cancer therapy is hampered by elements of the immunosuppressive tumor microenvironment such as TGF-ß. Here we demonstrate that FIST15, a recombinant chimeric protein composed of the T cell stimulatory cytokine IL-15, the sushi domain of IL15Rα and a TGF-β ligand trap, can overcome immunosuppressive TGF-β to effectively stimulate the proliferation and activation of natural killer (NK) and CD8+ T cells with potent antitumor properties. FIST15-treated NK and CD8+ T cells produced more IFNγ and TNFα compared to treatment with IL-15 and a commercially available TGF-β receptor-Fc fusion protein (sTβRII) in the presence of TGF-β. Murine B16 melanoma cells which overproduce TGF-β were lysed by FIST15-treated NK cells in vitro at doses ~10-fold lower than NK cells treated with IL-15 and sTβRII. Melanoma cells transduced to express FIST15 failed to establish tumors in vivo in immunocompetent murine hosts and could only form tumors in beige mice lacking NK cells. Mice injected with the same cells were also protected from subsequent challenge by unmodified B16 melanoma cells. Lastly, mice with pre-established B16 melanoma tumors responded to FIST15 treatment more strongly compared to tumors treated with control cytokines. Taken together, our results offer a preclinical proof of concept for the use of FIST15 as a new class of biological therapeutics that can coordinately neutralize the effects of immunosuppressive TGF-β in the tumor microvironment while empowering tumor immunity.

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Inhibition of TGF-β1 Signaling Promotes Central Memory T Cell Differentiation

Cited by 29 publications

References 31 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

Transforming growth factor-β signaling is constantly shaping memory T-cell population

Stimulation of Natural Killer Cell–Mediated Tumor Immunity by an IL15/TGFβ–Neutralizing Fusion Protein

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