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  1. Article ; Online: Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters

    Wataru Nishi / Ei Wakamatsu / Hiroaki Machiyama / Ryohei Matsushima / Kensho Saito / Yosuke Yoshida / Tetsushi Nishikawa / Tomohiro Takehara / Hiroko Toyota / Masae Furuhata / Hitoshi Nishijima / Arata Takeuchi / Miyuki Azuma / Makoto Suzuki / Tadashi Yokosuka

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 16

    Abstract: Abstract With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical ... ...

    Abstract Abstract With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments.
    Keywords Science ; Q
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: PD-L2 suppresses T cell signaling via coinhibitory microcluster formation and SHP2 phosphatase recruitment

    Tomohiro Takehara / Ei Wakamatsu / Hiroaki Machiyama / Wataru Nishi / Katsura Emoto / Miyuki Azuma / Kenzo Soejima / Koichi Fukunaga / Tadashi Yokosuka

    Communications Biology, Vol 4, Iss 1, Pp 1-

    2021  Volume 12

    Abstract: Takehara et al performed imaging analysis of microcluster formation between the PD-L1 and PD-L2, which are known to play a role in T cell activation in response to tumour cell signaling. Their analysis showed that the cluster formation inhibited T cell ... ...

    Abstract Takehara et al performed imaging analysis of microcluster formation between the PD-L1 and PD-L2, which are known to play a role in T cell activation in response to tumour cell signaling. Their analysis showed that the cluster formation inhibited T cell receptor signaling and could serve as a visual index for PD-L1/2-targeted cancer therapies.
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

    Masahiro Okada / Shunsuke Chikuma / Taisuke Kondo / Sana Hibino / Hiroaki Machiyama / Tadashi Yokosuka / Miyako Nakano / Akihiko Yoshimura

    Cell Reports, Vol 20, Iss 5, Pp 1017-

    2017  Volume 1028

    Abstract: Summary: Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing ... ...

    Abstract Summary: Programmed cell death 1 (PD-1) is highly expressed on exhausted T cells and inhibits T cell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse T cell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted T cells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Inhibition of Fut8, a core fucosyltransferase, by genetic ablation or pharmacologic inhibition reduced cell-surface expression of PD-1 and enhanced T cell activation, leading to more efficient tumor eradication. Taken together, our findings suggest that blocking core fucosylation of PD-1 can be a promising strategy for improving anti-tumor immune responses. : Using a genome-wide loss-of-function screening method, Okada et al. identify genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Keywords: PD-1, core fucosylation, CRISPR screen, tumor immunotherapy
    Keywords Biology (General) ; QH301-705.5
    Language English
    Publishing date 2017-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Role of interleukin-25 in development of spontaneous arthritis in interleukin-1 receptor antagonist-deficient mice

    Yasuharu Abe / Aya Nambu / Sachiko Yamaguchi / Ayako Takamori / Hajime Suto / Sachiko Hirose / Tadashi Yokosuka / Susumu Nakae / Katsuko Sudo

    Biochemistry and Biophysics Reports, Vol 12, Iss C, Pp 62-

    2017  Volume 65

    Abstract: Interleukin (IL)-25, which is a member of the IL-17 family of cytokines, induces production of such Th2 cytokines as IL-4, IL-5, IL-9 and/or IL-13 by various types of cells, including Th2 cells, Th9 cells and group 2 innate lymphoid cells (ILC2). On the ... ...

    Abstract Interleukin (IL)-25, which is a member of the IL-17 family of cytokines, induces production of such Th2 cytokines as IL-4, IL-5, IL-9 and/or IL-13 by various types of cells, including Th2 cells, Th9 cells and group 2 innate lymphoid cells (ILC2). On the other hand, IL-25 can suppress Th1- and Th17-associated immune responses by enhancing Th2-type immune responses. Supporting this, IL-25 is known to suppress development of experimental autoimmune encephalitis, which is an IL-17-mediated autoimmune disease in mice. However, the role of IL-25 in development of IL-17-mediated arthritis is not fully understood. Therefore, we investigated this using IL-1 receptor antagonist-deficient (IL-1Ra-/-) mice, which spontaneously develop IL-17-dependent arthritis. However, development of spontaneous arthritis (incidence rate, disease severity, proliferation of synovial cells, infiltration of PMNs, and bone erosion in joints) and differentiation of Th17 cells in draining lymph nodes in IL-25-/- IL-1Ra-/- mice were similar to in control IL-25+/+ IL-1Ra-/- mice. These observations indicate that IL-25 does not exert any inhibitory and/or pathogenic effect on development of IL-17-mediated spontaneous arthritis in IL-1Ra-/- mice.
    Keywords Biology (General) ; QH301-705.5 ; Biochemistry ; QD415-436
    Subject code 610
    Language English
    Publishing date 2017-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

    Full text online

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    Inter-library loan at ZB MED

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