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  1. Article: Targeting the Tumor Microenvironment for Improving Therapeutic Effectiveness in Cancer Immunotherapy: Focusing on Immune Checkpoint Inhibitors and Combination Therapies.

    Chyuan, I-Tsu / Chu, Ching-Liang / Hsu, Ping-Ning

    Cancers

    2021  Volume 13, Issue 6

    Abstract: Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in ... ...

    Abstract Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy.
    Language English
    Publishing date 2021-03-10
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers13061188
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Increased HIF-1α expression in T cells and associated with enhanced Th17 pathway in systemic lupus erythematosus.

    Liao, Hsiu-Jung / Chu, Ching-Liang / Wang, Szu-Chieh / Lee, Hua-Yi / Wu, Chien-Sheng

    Journal of the Formosan Medical Association = Taiwan yi zhi

    2022  Volume 121, Issue 12, Page(s) 2446–2456

    Abstract: Background/purpose: Recent emerging evidence indicates that dysfunction of metabolic remodeling underlies aberrant T cell immune responses in systemic lupus erythematosus (SLE). This study was undertaken to investigate the expression of HIF-1α, a ... ...

    Abstract Background/purpose: Recent emerging evidence indicates that dysfunction of metabolic remodeling underlies aberrant T cell immune responses in systemic lupus erythematosus (SLE). This study was undertaken to investigate the expression of HIF-1α, a regulator of metabolic reprogramming, in T cells from SLE.
    Methods: HIF-1α expression in T lymphocytes from SLE patients was examined by quantitative polymerase chain reaction (PCR) and the protein expression was analyzed with intracellular staining in flow cytometry. HIF-1α was overexpressed in murine CD4 T cells via transducing T cells with HIF-1α containing lentivirus. The expression of HIF-1α, metabolic- and Th17-associated genes in T cells from SLE patients and its association with clinical manifestation was analyzed.
    Results: HIF-1α expression is increased in CD4 T cells from SLE patients both in intracellular staining and quantitative PCR analysis. In addition, there is enhanced HIF-1α expression in Th17-skewing murine T cells, and lentivirus-mediated HIF-1α overexpression promotes Th17 differentiation. Moreover, HIF-1α gene expression is positively correlated with the expression of glycolysis- and IL-17-associated genes in SLE patients.
    Conclusion: HIF-1α expression is increased in T cells from SLE patients, and is positively correlated with glycolysis- and Th17- associated pathway, implicating HIF-1α contributes to the activation of Th17 cells in SLE, and represents a potential novel therapeutic target.
    MeSH term(s) Humans ; Mice ; Animals ; Th17 Cells/metabolism ; Lupus Erythematosus, Systemic/drug therapy ; CD4-Positive T-Lymphocytes/metabolism ; Flow Cytometry ; Cell Differentiation
    Language English
    Publishing date 2022-05-20
    Publishing country Singapore
    Document type Journal Article
    ZDB-ID 2096659-3
    ISSN 1876-0821 ; 0929-6646
    ISSN (online) 1876-0821
    ISSN 0929-6646
    DOI 10.1016/j.jfma.2022.05.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Ling Zhi-8, a fungal immunomodulatory protein in

    Li, Ju-Pi / Chu, Ching-Liang / Chao, Wan-Ru / Yeh, Cheng-Siang / Lee, Yi-Ju / Chen, Dz-Chi / Yang, Shun-Fa / Chao, Yu-Hua

    Aging

    2023  Volume 15, Issue 9, Page(s) 3621–3634

    Abstract: CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal ... ...

    Abstract CPT-11 (Irinotecan) remains an important chemotherapeutic agent against various solid tumors nowadays. Potential adverse effects, especially gastrointestinal toxicities, are the main limiting factor for its clinical utility. Ling Zhi-8 (LZ-8), a fungal immunomodulatory protein in
    MeSH term(s) Mice ; Animals ; Reishi ; Irinotecan ; Claudin-1/genetics
    Chemical Substances Irinotecan (7673326042) ; Claudin-1
    Language English
    Publishing date 2023-05-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1945-4589
    ISSN (online) 1945-4589
    DOI 10.18632/aging.204695
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: SHP-1 (PTPN6) keeps the inflammation at bay: limiting IL-1α-mediated neutrophilic dermatoses by preventing Syk kinase activation.

    You, Ren-In / Chu, Ching-Liang

    Cellular & molecular immunology

    2017  

    Language English
    Publishing date 2017-07-10
    Publishing country China
    Document type Journal Article
    ZDB-ID 2435097-7
    ISSN 2042-0226 ; 1672-7681
    ISSN (online) 2042-0226
    ISSN 1672-7681
    DOI 10.1038/cmi.2017.59
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: MyD88 exacerbates inflammation-induced bone loss by modulating dynamic equilibrium between Th17/Treg cells and subgingival microbiota dysbiosis.

    Hsiao, Po-Yan / Huang, Ren-Yeong / Huang, Lin-Wei / Chu, Ching-Liang / Dyke, Thomas Van / Mau, Lian-Ping / Cheng, Chia-Dan / Sung, Cheng-En / Weng, Pei-Wei / Wu, Yu-Chiao / Shieh, Yi-Shing / Cheng, Wan-Chien

    Journal of periodontology

    2024  

    Abstract: Background: This study aimed to investigate the contribution of myeloid differentiation primary-response gene 88 (MyD88) on the differentiation of T helper type 17 (Th17) and regulatory T (Treg) cells and the emerging subgingival microbiota dysbiosis in ...

    Abstract Background: This study aimed to investigate the contribution of myeloid differentiation primary-response gene 88 (MyD88) on the differentiation of T helper type 17 (Th17) and regulatory T (Treg) cells and the emerging subgingival microbiota dysbiosis in Porphyromonas gingivalis-induced experimental periodontitis.
    Methods: Alveolar bone loss, infiltrated inflammatory cells, immunostained cells for tartrate-resistant acid phosphatase (TRAP), the receptor activator of nuclear factor-kB ligand (RANKL), and osteoprotegerin (OPG) were quantified by microcomputerized tomography and histological staining between age- and sex-matched homozygous littermates (wild-type [WT, Myd88
    Results: P. gingivalis-infected Myd88
    Conclusions: MyD88 plays an important role in inflammation-induced bone loss by modulating the dynamic equilibrium between Th17/Treg cells and dysbiosis in P. gingivalis-induced experimental periodontitis.
    Language English
    Publishing date 2024-03-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 390921-9
    ISSN 1943-3670 ; 0022-3492 ; 1049-8885 ; 0095-960X
    ISSN (online) 1943-3670
    ISSN 0022-3492 ; 1049-8885 ; 0095-960X
    DOI 10.1002/JPER.23-0561
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Association of TRAIL receptor with phosphatase SHP-1 enables repressing T cell receptor signaling and T cell activation through inactivating Lck.

    Chyuan, I-Tsu / Liao, Hsiu-Jung / Tan, Tse-Hua / Chuang, Huai-Chia / Chu, Yu-Chuan / Pan, Meng-Hsun / Wu, Chien-Sheng / Chu, Ching-Liang / Sheu, Bor-Ching / Hsu, Ping-Ning

    Journal of biomedical science

    2024  Volume 31, Issue 1, Page(s) 33

    Abstract: Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to ... ...

    Abstract Background: T cell receptor (TCR) signaling and T cell activation are tightly regulated by gatekeepers to maintain immune tolerance and avoid autoimmunity. The TRAIL receptor (TRAIL-R) is a TNF-family death receptor that transduces apoptotic signals to induce cell death. Recent studies have indicated that TRAIL-R regulates T cell-mediated immune responses by directly inhibiting T cell activation without inducing apoptosis; however, the distinct signaling pathway that regulates T cell activation remains unclear. In this study, we screened for intracellular TRAIL-R-binding proteins within T cells to explore the novel signaling pathway transduced by TRAIL-R that directly inhibits T cell activation.
    Methods: Whole-transcriptome RNA sequencing was used to identify gene expression signatures associated with TRAIL-R signaling during T cell activation. High-throughput screening with mass spectrometry was used to identify the novel TRAIL-R binding proteins within T cells. Co-immunoprecipitation, lipid raft isolation, and confocal microscopic analyses were conducted to verify the association between TRAIL-R and the identified binding proteins within T cells.
    Results: TRAIL engagement downregulated gene signatures in TCR signaling pathways and profoundly suppressed phosphorylation of TCR proximal tyrosine kinases without inducing cell death. The tyrosine phosphatase SHP-1 was identified as the major TRAIL-R binding protein within T cells, using high throughput mass spectrometry-based proteomics analysis. Furthermore, Lck was co-immunoprecipitated with the TRAIL-R/SHP-1 complex in the activated T cells. TRAIL engagement profoundly inhibited phosphorylation of Lck (Y394) and suppressed the recruitment of Lck into lipid rafts in the activated T cells, leading to the interruption of proximal TCR signaling and subsequent T cell activation.
    Conclusions: TRAIL-R associates with phosphatase SHP-1 and transduces a unique and distinct immune gatekeeper signal to repress TCR signaling and T cell activation via inactivating Lck. Thus, our results define TRAIL-R as a new class of immune checkpoint receptors for restraining T cell activation, and TRAIL-R/SHP-1 axis can serve as a potential therapeutic target for immune-mediated diseases.
    MeSH term(s) Humans ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Receptors, Antigen, T-Cell/metabolism ; Jurkat Cells ; Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism ; Signal Transduction ; Protein Tyrosine Phosphatases/genetics ; Protein Tyrosine Phosphatases/metabolism ; Phosphorylation ; Lymphocyte Activation ; Tyrosine/metabolism
    Chemical Substances Receptors, TNF-Related Apoptosis-Inducing Ligand ; Receptors, Antigen, T-Cell ; Protein Tyrosine Phosphatase, Non-Receptor Type 6 (EC 3.1.3.48) ; Protein Tyrosine Phosphatases (EC 3.1.3.48) ; Tyrosine (42HK56048U)
    Language English
    Publishing date 2024-03-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 1193378-1
    ISSN 1423-0127 ; 1021-7770
    ISSN (online) 1423-0127
    ISSN 1021-7770
    DOI 10.1186/s12929-024-01023-8
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  7. Article ; Online: A recently described type 2 conventional dendritic cell (cDC2) subset mediates inflammation.

    Shin, Jenn-Yeu / Wang, Chen-Yu / Lin, Chi-Chien / Chu, Ching-Liang

    Cellular & molecular immunology

    2020  Volume 17, Issue 12, Page(s) 1215–1217

    MeSH term(s) Dendritic Cells ; Humans ; Inflammation ; Macrophages ; Virus Diseases
    Language English
    Publishing date 2020-07-30
    Publishing country China
    Document type Journal Article ; Comment
    ZDB-ID 2435097-7
    ISSN 2042-0226 ; 1672-7681
    ISSN (online) 2042-0226
    ISSN 1672-7681
    DOI 10.1038/s41423-020-0511-y
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: T Cell-Specific Deletion of TRAIL Receptor Reveals Its Critical Role for Regulating Pathologic T Cell Activation and Disease Induction in Experimental Autoimmune Encephalomyelitis.

    Chyuan, I-Tsu / Chu, Ching-Liang / Hsu, Chia-Lang / Pan, Meng-Hsun / Liao, Hsiu-Jung / Wu, Chien-Sheng / Hsu, Ping-Ning

    Journal of immunology (Baltimore, Md. : 1950)

    2022  Volume 208, Issue 7, Page(s) 1534–1544

    Abstract: Recent evidence from several autoimmune animal models has demonstrated that TRAIL suppresses the activation of T cells and inhibits autoimmune inflammation via an apoptosis-independent pathway. However, it remains unclear whether the immunosuppressive ... ...

    Abstract Recent evidence from several autoimmune animal models has demonstrated that TRAIL suppresses the activation of T cells and inhibits autoimmune inflammation via an apoptosis-independent pathway. However, it remains unclear whether the immunosuppressive effects of TRAIL are dependent on its direct effects on T cells or on other immune cells to regulate T cells for the induction of disease. Therefore, we generated mice with T cell-specific TRAIL receptor (TRAIL-R) conditional knockout to investigate the impact of TRAIL on autoimmune inflammation and disease induction in experimental autoimmune encephalomyelitis (EAE). T cell-specific TRAIL-R knockout mice were found to completely reverse the TRAIL-mediated suppression of inflammation and disease induction, indicating that TRAIL-R on T cells is essential for TRAIL-mediated suppression of inflammation and disease induction in EAE. Moreover, the immune suppression effects were not due to the induction of cell apoptosis, but to the direct inhibition of T cell activation. In addition, RNA sequencing and transcriptome analysis revealed that TRAIL-R signaling significantly downregulated the genes involved in TCR signaling pathways, T cell differentiation, and proinflammatory cytokines. These results indicate that TRAIL-R on T cells is critical for pathologic T cell activation and induction of inflammation in EAE, suggesting that TRAIL-R serves as a novel immune checkpoint receptor in T cell-mediated autoimmune diseases.
    MeSH term(s) Animals ; Encephalomyelitis, Autoimmune, Experimental ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes ; TNF-Related Apoptosis-Inducing Ligand
    Chemical Substances TNF-Related Apoptosis-Inducing Ligand
    Language English
    Publishing date 2022-03-09
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100788
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  9. Article: The Enhancing Effect of Fungal Immunomodulatory Protein-Volvariella Volvacea (FIP-vvo) on Maturation and Function of Mouse Dendritic Cells.

    Li, Ju-Pi / Lee, Yi-Pang / Ma, Jung-Chein / Liu, Betty-Revon / Hsieh, Nien-Tsu / Chen, Dz-Chi / Chu, Ching-Liang / You, Ren-In

    Life (Basel, Switzerland)

    2021  Volume 11, Issue 6

    Abstract: Volvariella volvacea, also known as straw mushroom, is a common edible mushroom in Chinese cuisine. It contains many nutrients for human health. A fungal immunomodulatory protein (FIP) has been isolated ... ...

    Abstract Volvariella volvacea, also known as straw mushroom, is a common edible mushroom in Chinese cuisine. It contains many nutrients for human health. A fungal immunomodulatory protein (FIP) has been isolated from
    Language English
    Publishing date 2021-05-24
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2662250-6
    ISSN 2075-1729
    ISSN 2075-1729
    DOI 10.3390/life11060471
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Tyrosine kinase inhibitors modulate dendritic cell activity via confining c-Kit signaling and tryptophan metabolism.

    Chu, Ching-Liang / Lee, Yi-Pang / Pang, Cheng-Yoong / Lin, Huei-Ru / Chen, Chang-Shan / You, Ren-In

    International immunopharmacology

    2020  Volume 82, Page(s) 106357

    Abstract: Dendritic cell (DC)-based vaccine has been established in tumor immunotherapy. Importantly, the efficiency of anti-tumor T-cells in draining lymph nodes is dependent on the status of DCs surrounding in tumors. It has been shown that Indoleamine 2,3- ... ...

    Abstract Dendritic cell (DC)-based vaccine has been established in tumor immunotherapy. Importantly, the efficiency of anti-tumor T-cells in draining lymph nodes is dependent on the status of DCs surrounding in tumors. It has been shown that Indoleamine 2,3-dioxygenase (IDO) plays a key role to induce tolerogenic DCs in tumor microenvironment, and tyrosine kinase inhibitors (TKIs) can suppress the function of IDO in DCs. However, the stimulatory effect of TKI-modified DCs on T cells remains unclear. In this report, we found that one type of TKI-dasatinib can modify DCs to increasing the activation of allogenic T cells. These TKI-modified DCs delayed the onset of B16 melanoma progression in mice. In mechanistic studies, TKIs did not increase the maturation but reduce the expression and phosphorylation levels of IDO and IDO mediated tryptophan metabolism in DCs. In addition, the suppressive effect of TKIs on tryptophan metabolism may be caused by blocking c-Kit pathway in DCs. Furthermore, the increased phosphorylation of general control nonderepressible (GCN2) and decreased expression of aryl hydrocarbon receptor (AhR)/aryl hydrocarbon receptor nuclear translocator (ARNT) were observed in the T cells activated by TKI-modified DCs, suggesting the enhancement of effector function of T cells. These results indicate that TKI could be used to modulate DC immunogenic activity and may potentially be applied in DC-based cancer immunotherapy.
    Language English
    Publishing date 2020-03-06
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2043785-7
    ISSN 1878-1705 ; 1567-5769
    ISSN (online) 1878-1705
    ISSN 1567-5769
    DOI 10.1016/j.intimp.2020.106357
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