Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular ...regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8
T cells, and also CD4
T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.
The liver is a lymphoid organ with unique immunological properties, particularly, its predominant innate immune system. The balance between immune tolerance and immune activity is critical to liver ...physiological functions and is responsible for the sensitivity of this organ to numerous diseases, including hepatotropic virus infection, alcoholic liver disease, nonalcoholic fatty liver disease, autoimmune liver disease, and liver cancer, which are major health problems globally. In the past decade, with the discovery of liver-resident natural killer cells, the importance of innate lymphocytes with tissue residency has gradually become the focus of research. In this review, we address the current knowledge regarding hepatic innate lymphocytes with unique characteristics, including NK cells, ILC1/2/3s, NKT cells, γδ T cells, and MAIT cells, and their potential roles in liver homeostasis maintenance and the progression of liver diseases and cancer. A better understanding of the immunopathogenesis of hepatic innate lymphocytes will be helpful for proposing effective treatments for liver diseases and cancer.
NK Cell Exhaustion Bi, Jiacheng; Tian, Zhigang
Frontiers in immunology,
06/2017, Letnik:
8
Journal Article
Recenzirano
Odprti dostop
Natural killer cells are important effector lymphocytes of the innate immune system, playing critical roles in antitumor and anti-infection host defense. Tumor progression or chronic infections, ...however, usually leads to exhaustion of NK cells, thus limiting the antitumor/infection potential of NK cells. In many tumors or chronic infections, multiple mechanisms might contribute to the exhaustion of NK cells, such as dysregulated NK cell receptors signaling, as well as suppressive effects by regulatory cells or soluble factors within the microenvironment. Better understanding of the characteristics, as well as the underlying mechanisms of NK cell exhaustion, not only should increase our understanding of the basic biology of NK cells but also could reveal novel NK cell-based antitumor/infection targets. Here, we provide an overview of our current knowledge on NK cell exhaustion in tumors, and in chronic infections.
The liver is an immunologically tolerant organ that is uniquely equipped to limit hypersensitivity to food-derived antigens and bacterial products through the portal vein and can feasibly accept ...liver allografts. The adaptive immune response is a major branch of the immune system that induces organ/tissue-localized and systematic responses against pathogens and tumors while promoting self-tolerance. Persistent infection of the liver with a virus or other pathogen typically results in tolerance, which is a key feature of the liver. The liver's immunosuppressive microenvironment means that hepatic adaptive immune cells become readily tolerogenic, promoting the death of effector cells and the "education" of regulatory cells. The above mechanisms may result in the clonal deletion, exhaustion, or inhibition of peripheral T cells, which are key players in the adaptive immune response. These tolerance mechanisms are believed to be responsible for almost all liver diseases. However, optimal protective adaptive immune responses may be achieved through checkpoint immunotherapy and the modulation of hepatic innate immune cells in the host. In this review, we focus on the mechanisms involved in hepatic adaptive immune tolerance, the liver diseases caused thereby, and the therapeutic strategies needed to overcome this tolerance.
NK cells play important roles in the innate immune responses against tumors. The effector function of NK cells relies on the integration of activating and inhibitory signals. Emerging checkpoint ...receptors and molecules are being revealed to mediate NK cell dysfunction in the tumor microenvironment. Inhibition of some NK cell surface checkpoint receptors has displayed the potential to reverse NK cell dysfunction in tumors, and to boost anti-tumor immunity, both in clinical trials (anti-KIR and anti-NKG2A), and in preclinical studies (e.g., anti-TIGIT, and anti-CD96). To fully exploit the potential of NK-based checkpoint immunotherapy, more understanding of the regional features of NK cells in the tumor microenvironment is required. This will provide valuable information regarding the dynamic nature of NK cell immune response against tumors, as well as novel checkpoints or pathways to be targeted. In this Review, we discuss recent advances in the understanding of NK cell dysfunction in tumors, as well as emerging strategies of NK-based checkpoint immunotherapy for tumors.
Natural killer （NK） cell education, a process for achieving functional maturation and self-tolerance, has been previously defined by the interaction between self-major histocompatibility complex ...class I （MHC-I） molecules and their specific inhibitory receptors. Over the past several years, growing evidence has highlighted the important roles of nonclassical MHC-I and non-MHC-I molecules in NK cell education. Herein, we review the current knowledge of NK cell education, with a particular focus on nonclassical MHC-I- and non-MHC-I-dependent education, and compare them with the classical MHC-I-dependent education theory. In addition, we update and extend this theory by presenting the ＇Confining Model＇, discussing cis and trans characteristics, reassessing quantity and quality control, and elucidating the redundancy of NK cell education in tumor and virus infection.
The efficacy of nano-mediated drug delivery has been impeded by multiple biological barriers such as the mononuclear phagocyte system (MPS), as well as vascular and interstitial barriers. To overcome ...the abovementioned obstacles, we report a nano-pathogenoid (NPN) system that can in situ hitchhike circulating neutrophils and supplement photothermal therapy (PTT). Cloaked with bacteria-secreted outer membrane vesicles inheriting pathogen-associated molecular patterns of native bacteria, NPNs are effectively recognized and internalized by neutrophils. The neutrophils migrate towards inflamed tumors, extravasate across the blood vessels, and penetrate through the tumors. Then NPNs are rapidly released from neutrophils in response to inflammatory stimuli and subsequently taken up by tumor cells to exert anticancer effects. Strikingly, due to the excellent targeting efficacy, cisplatin-loaded NPNs combined with PTT completely eradicate tumors in all treated mice. Such a nano-platform represents an efficient and generalizable strategy towards in situ cell hitchhiking as well as enhanced tumor targeted delivery.
The objective of condition based maintenance (CBM) is typically to determine an optimal maintenance policy to minimize the overall maintenance cost based on condition monitoring information. The ...existing work reported in the literature only focuses on determining the optimal CBM policy for a single unit. In this paper, we investigate CBM of multi-component systems, where economic dependency exists among different components subject to condition monitoring. The fixed preventive replacement cost, such as sending a maintenance team to the site, is incurred once a preventive replacement is performed on one component. As a result, it would be more economical to preventively replace multiple components at the same time. In this work, we propose a multi-component system CBM policy based on proportional hazards model (PHM). The cost evaluation of such a CBM policy becomes much more complex when we extend the PHM based CBM policy from a single unit to a multi-component system. A numerical algorithm is developed in this paper for the exact cost evaluation of the PHM based multi-component CBM policy. Examples using real-world condition monitoring data are provided to demonstrate the proposed methods.
Natural killer (NK) cells are effective in combating infections and tumors and as such are tempting for adoptive transfer therapy. However, they are not homogeneous but can be divided into three main ...subsets, including cytotoxic, tolerant, and regulatory NK cells, with disparate phenotypes and functions in diverse tissues. The development and functions of such NK cells are controlled by various cytokines, such as fms-like tyrosine kinase 3 ligand (FL), kit ligand (KL), interleukin (IL)-3, IL-10, IL-12, IL-18, transforming growth factor-β, and common-γ chain family cytokines, which operate at different stages by regulating distinct signaling pathways. Nevertheless, the specific roles of each cytokine that regulates NK cell development or that shapes different NK cell functions remain unclear. In this review, we attempt to describe the characteristics of each cytokine and the existing protocols to expand NK cells using different combinations of cytokines and feeder cells. A comprehensive understanding of the role of cytokines in NK cell development and function will aid the generation of better efficacy for adoptive NK cell treatment.
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