The Experts below are selected from a list of 17013 Experts worldwide ranked by ideXlab platform
Dmitry I. Gabrilovich - One of the best experts on this subject based on the ideXlab platform.
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Tumor Escape Mechanism Governed by Myeloid-Derived Suppressor Cells
Cancer Research, 2008Co-Authors: Srinivas Nagaraj, Dmitry I. GabrilovichAbstract:T-cell nonresponsiveness is a critical factor in immune Escape and myeloid-derived suppressor cells play a major role in organizing this phenomenon. Recent findings indicate that myeloid-derived suppressor cells can induce antigen-specific CD8+ T-cell tolerance through a posttranslation mechanism which involves modification (nitration) of CD8 and the T-cell receptor itself on the T-cell surface. Elucidation of this mechanism of T-cell tolerance offers new opportunities for therapeutic corrections of immune Escape in cancer. [Cancer Res 2008;68(8):2561–63]
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altered recognition of antigen is a mechanism of cd8 t cell tolerance in cancer
Nature Medicine, 2007Co-Authors: Srinivas Nagaraj, Kapil Gupta, Vladimir Pisarev, Leo Kinarsky, Simon Sherman, Loveleen Kang, Donna L Herber, Jonathan P Schneck, Dmitry I. GabrilovichAbstract:Antigen-specific CD8+ T-cell tolerance, induced by myeloid-derived suppressor cells (MDSCs), is one of the main mechanisms of Tumor Escape. Using in vivo models, we show here that MDSCs directly disrupt the binding of specific peptide–major histocompatibility complex (pMHC) dimers to CD8-expressing T cells through nitration of tyrosines in a T-cell receptor (TCR)-CD8 complex. This process makes CD8-expressing T cells unable to bind pMHC and to respond to the specific peptide, although they retain their ability to respond to nonspecific stimulation. Nitration of TCR-CD8 is induced by MDSCs through hyperproduction of reactive oxygen species and peroxynitrite during direct cell-cell contact. Molecular modeling suggests specific sites of nitration that might affect the conformational flexibility of TCR-CD8 and its interaction with pMHC. These data identify a previously unknown mechanism of T-cell tolerance in cancer that is also pertinent to many pathological conditions associated with accumulation of MDSCs.
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Myeloid-Derived Suppressor Cells
Advances in Experimental Medicine and Biology, 2007Co-Authors: Srinivas Nagaraj, Dmitry I. GabrilovichAbstract:The development of Tumor-specific T cell tolerance is largely responsible for Tumor Escape. Accumulation of myeloid-derived suppressor cells (MDSCs) in animal Tumor models as well as in cancer patients is involved in Tumor-associated T cell tolerance. In recent years, it has become increasingly evident that MDSCs bring about antigen-specific T cell tolerance by various mechanisms, which is the focus of this chapter.
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effect of Tumor derived cytokines and growth factors on differentiation and immune suppressive features of myeloid cells in cancer
Cancer and Metastasis Reviews, 2006Co-Authors: Sergei Kusmartsev, Dmitry I. GabrilovichAbstract:It is well established that cancers affect differentiation of dendritic cells and promote systemic expansion of immune suppressive immature myeloid cells. This phenomenon may represent a mechanism of Tumor Escape from immune attack and could have significant impact on Tumor progression. In this review we discuss the role of different Tumor-derived factors, which were implicated in abnormal myeloid cell differentiation. The role of reactive oxygen species as well as JAK/STAT signaling in mechanisms of the effects of Tumor-derived factors on myeloid cells is also discussed.
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Tumor-Associated CD8+ T Cell Tolerance Induced by Bone Marrow-Derived Immature Myeloid Cells
The Journal of Immunology, 2005Co-Authors: Sergei Kusmartsev, Srinivas Nagaraj, Dmitry I. GabrilovichAbstract:T cell tolerance is a critical element of Tumor Escape. However, the mechanism of Tumor-associated T cell tolerance remains unresolved. Using an experimental system utilizing the adoptive transfer of transgenic T cells into naive recipients, we found that the population of Gr-1+ immature myeloid cells (ImC) from Tumor-bearing mice was able to induce CD8+ T cell tolerance. These ImC accumulate in large numbers in spleens, lymph nodes, and Tumor tissues of Tumor-bearing mice and are comprised of precursors of myeloid cells. Neither ImC from control mice nor progeny of Tumor-derived ImC, including Tumor-derived CD11c+ dendritic cells, were able to render T cells nonresponsive. ImC are able to take up soluble protein in vivo, process it, and present antigenic epitopes on their surface and induce Ag-specific T cell anergy. Thus, this is a first demonstration that in Tumor-bearing mice CD8+ T cell tolerance is induced primarily by ImC that may have direct implications for cancer immunotherapy.
Xianjie Jiang - One of the best experts on this subject based on the ideXlab platform.
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role of the Tumor microenvironment in pd l1 pd 1 mediated Tumor immune Escape
Molecular Cancer, 2019Co-Authors: Xianjie Jiang, Jie Wang, Xiangying Deng, Fang Xiong, Bo Xiang, Ming Zhou, Wei XiongAbstract:Tumor immune Escape is an important strategy of Tumor survival. There are many mechanisms of Tumor immune Escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of Tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of Tumor cells, thereby achieving Tumor immune Escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the Tumor microenvironment and their roles in mediating Tumor Escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the Tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
Thomas F Gajewski - One of the best experts on this subject based on the ideXlab platform.
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the egr2 targets lag 3 and 4 1bb describe and regulate dysfunctional antigen specific cd8 t cells in the Tumor microenvironment
Journal of Experimental Medicine, 2017Co-Authors: Jason B Williams, Brendan Horton, Yan Zheng, Yukan Duan, Jonathan D Powell, Thomas F GajewskiAbstract:Although the presence of Tumor-infiltrating lymphocytes (TILs) indicates an endogenous antiTumor response, immune regulatory pathways can subvert the effector phase and enable Tumor Escape. Negative regulatory pathways include extrinsic suppression mechanisms, but also a T cell–intrinsic dysfunctional state. A more detailed study has been hampered by a lack of cell surface markers defining Tumor-specific dysfunctional TILs, and PD-1 alone is not sufficient. Recently, we identified the transcription factor Egr2 as a critical component in controlling the anergic state in vitro. In this study, we show that the Egr2-driven cell surface proteins LAG-3 and 4-1BB can identify dysfunctional Tumor antigen–specific CD8+ TIL. Co-expression of 4-1BB and LAG-3 was seen on a majority of CD8+ TILs, but not in lymphoid organs. Functional analysis revealed defective IL-2 and TNF production yet retained expression of IFN-γ and regulatory T cell–recruiting chemokines. Transcriptional and phenotypic characterization revealed coexpression of multiple additional co-stimulatory and co-inhibitory receptors. Administration of anti–LAG-3 plus anti–4-1BB mAbs was therapeutic against Tumors in vivo, which correlated with phenotypic normalization. Our results indicate that coexpression of LAG-3 and 4-1BB characterize dysfunctional T cells within Tumors, and that targeting these receptors has therapeutic utility.
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innate and adaptive immune cells in the Tumor microenvironment
Nature Immunology, 2013Co-Authors: Thomas F Gajewski, Hans SchreiberAbstract:Most Tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antiTumor immune responses to grow progressively. Recent work has suggested two broad categories of Tumor Escape based on cellular and molecular characteristics of the Tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These Tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of Tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.
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up regulation of pd l1 ido and t regs in the melanoma Tumor microenvironment is driven by cd8 t cells
Science Translational Medicine, 2013Co-Authors: Stefani Spranger, Jason B Williams, Robbert M Spaapen, Yuanyuan Zha, Yuru Meng, Thanh T Ha, Thomas F GajewskiAbstract:Tumor Escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8 + T cells, can be found in a subset of patients, those Tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed Tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3 + regulatory T cells (T regs ), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8 + T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of T regs , in the Tumor microenvironment depended on the presence of CD8 + T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed Tumor microenvironment.
Wei Xiong - One of the best experts on this subject based on the ideXlab platform.
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role of the Tumor microenvironment in pd l1 pd 1 mediated Tumor immune Escape
Molecular Cancer, 2019Co-Authors: Xianjie Jiang, Jie Wang, Xiangying Deng, Fang Xiong, Bo Xiang, Ming Zhou, Wei XiongAbstract:Tumor immune Escape is an important strategy of Tumor survival. There are many mechanisms of Tumor immune Escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of Tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of Tumor cells, thereby achieving Tumor immune Escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the Tumor microenvironment and their roles in mediating Tumor Escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the Tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
Ming Zhou - One of the best experts on this subject based on the ideXlab platform.
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role of the Tumor microenvironment in pd l1 pd 1 mediated Tumor immune Escape
Molecular Cancer, 2019Co-Authors: Xianjie Jiang, Jie Wang, Xiangying Deng, Fang Xiong, Bo Xiang, Ming Zhou, Wei XiongAbstract:Tumor immune Escape is an important strategy of Tumor survival. There are many mechanisms of Tumor immune Escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of Tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of Tumor cells, thereby achieving Tumor immune Escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the Tumor microenvironment and their roles in mediating Tumor Escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the Tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
