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Investigating and harnessing T-cell functions with engineered immune receptors and their ligands

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889194131 Year: Pages: 191 DOI: 10.3389/978-2-88919-413-1 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-12-10 11:59:06
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T-cells are an essential component of the immune system that provide protection against pathogen infections and cancer and are involved in the aetiology of numerous autoimmune and autoinflammatory pathologies. Their importance in disease, the relative ease to isolate, expand and manipulate them ex vivo have put T-cells at the forefront of basic and translational research in immunology. Decades of study have shed some light on the unique way T-cells integrate extrinsic environmental cues influencing an activation program triggered by interactions between peptide-MHC complexes and the antigen-recognition machinery constituted of clonally distributed T-cell receptors and their co-receptor CD4 or CD8. The manipulation of these molecular determinants in cellular systems or as recombinant proteins has considerably enhanced our ability to understand antigen-specific T-cell activation, to monitor ongoing T-cell responses and to exploit T-cells for therapy. Even though these principles have given numerous insights in the biology of CD8+ T-cells that translate into promising therapeutic prospects, as illustrated by recent breakthroughs in cancer therapy, they have proven more challenging to apply to CD4+ T-cells.This Research Topics aims to provide a comprehensive view of the recent insights provided by the use of engineered antigen receptors and their ligands on T-cell activation and how they have been or could be harnessed to design efficient immunotherapies.

Structural and computational glycobiology: immunity and infection

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196388 Year: Pages: 102 DOI: 10.3389/978-2-88919-638-8 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2015-10-30 16:33:44
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Interest in understanding the biological role of carbohydrates has increased significantly over the last 20 years. The use of structural techniques to understand carbohydrate-protein recognition is still a relatively young area, but one that is of emerging importance. The high flexibility of carbohydrates significantly complicates the determination of high quality structures of their complexes with proteins. Specialized techniques are often required to understand the complexity of carbohydrate recognition by proteins. In this Research Topic, we will focus on structural and computational approaches to understanding carbohydrate recognition by proteins involved in immunity and infection. Particular areas of focus include cancer immunotherapeutics, carbohydrate-lectin interactions, glycosylation and glycosyltransferases.

Tumor Cell/Dendritic Cell Interactions and the Influence of Tumors on Dendritic Cell-mediated Anti-Tumor Immune Responses and Dendritic Cell-Based Tumor Immunotherapies

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889192458 Year: Pages: 160 DOI: 10.3389/978-2-88919-245-8 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology --- Oncology
Added to DOAB on : 2015-11-16 15:44:59
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Significant efforts over the last two decades have been made to better understand the factors that control DC maturation and activation and the impact of these processes on overall host immunity. In addition to the well-characterized role of DC in the induction of immunity to pathogens, a role for these cells as critical regulators of anti-tumor immune responses has more recently become apparent. These findings have generated interest in understanding how tumor/DC interactions impact the quality of anti-tumor immune responses, and they have contributed to increased enthusiasm for a variety of DC-based cancer immunotherapies. Such strategies have included DNA- or peptide-based vaccines that involve uptake and processing of tumor antigens by endogenous DC in cancer patients or the administration of tumor antigen-loaded exogenous DC-based vaccines. Additionally, many adjuvant, cytokine, and monoclonal antibody therapies aim either to enhance the immunostimulatory capacity of endogenous DC or to supplement the activity of these cells by targeting costimulatory receptors on T cells. Despite the promise of such therapeutic approaches for cancer treatment, their success is often limited, and much remains to be understood about how tumors influence DC function and the quality of DC-mediated immune responses. Tumor/DC interactions have therefore become an increasingly active area of investigation, and many studies have described effects of tumors on DC phenotype and function that include an accumulation of immature DC within tumors, tumor-altered differentiation of DC precursors into myeloid-derived suppressor cells, and the generation of tumor-associated DC with immunoregulatory properties. As this field moves forward, it will be important to gain mechanistic insights into the basis for both tumor-mediated DC dysfunction as well as the induction of either suboptimal or immunosuppressive adaptive anti-tumor immune responses by tumor-associated DC. Progress in these areas of tumor immunology will greatly improve our understanding of the factors that contribute to effective DC-mediated anti-tumor immune control versus DC-associated anti-tumor immune dysfunction and subsequent tumor immune escape. Such information is vital for improving current and developing novel immunotherapeutic strategies for interfering with tumor-associated DC dysfunction and enhancing the functional quality of endogenous DC in cancer patients as well as the efficacy of exogenous DC-based anti-tumor vaccines. The articles contained within this special issue highlight these important topics and bring focus not only to our current understanding of tumor/DC interactions but also to major areas of investigation that remain ongoing in this field.

Cancer Immunotherapy & Immuno-monitoring: Mechanism, Treatment, Diagnosis, and Emerging Tools

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889193806 Year: Pages: 97 DOI: 10.3389/978-2-88919-380-6 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Medicine (General)
Added to DOAB on : 2015-12-03 13:02:24
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In the past decade, significant progresses have taken place in the field of cancer immunotherapy. Tumor-targeting immunotherapies are being developed for most human cancers, including melanoma, prostate cancer, glioblastoma, sarcoma, lung carcinoma and hepatocellular carcinoma. The FDA has approved multiple molecular immunotherapeutics, such as Ipilimumab; cellular immunotherapies (e.g. adoptive cell transfer) are being tested in phase II/III clinical trials. Immunotherapetics has evolved into a sophisticated field: Multimodal therapeutic regimens are administrated to induce focused responses, curtail side- effects and improve therapeutic efficacy. The lack of effective clinical assessment tools remains a major challenge. Because of the intricacy of antitumor response, it is essential to scrutinize individual tumor-targeting immune cells and their functions at the finest details - molecules. In this regard, flow cytometry analysis modernized hematology and allows characterization of surface molecular signature on individual cells. More recently, microchip technologies and new variations of cytometry have enormously expanded the spectrum, throughout and multiplexity of single cell analysis. Nowadays, tens of millions of readouts can be generated through the course of a cancer immunotherapy to monitor the abundance, phenotype and a myriad of effector functions of single immune cells. At the same time, big data analytics and data mining methodologies have been adapted to achieve sensible diagnostic interpretations. Such a marriage of technology and analytics opens the door for informative point-of-care assessment of therapeutic efficacy and ensures timely therapeutic decisions. The new generation of personalized clinical diagnostics will revolutionize healthcare in the years to come.

NK Cell-Based Cancer Immunotherapy

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889199341 Year: Pages: 222 DOI: 10.3389/978-2-88919-934-1 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-01-19 14:05:46
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Natural killer (NK) cells are innate lymphoid cells that have a significant role in regulating the defenses against cancer development and certain viral infections. They are equipped with an array of activating and inhibitory receptors that stimulate or diminish NK cell activity, respectively. Inhibitory receptors include, among others, the MHC class I ligands killer cell immunoglobulin-like receptors (KIR) in humans, and members of the Ly49 family of receptors in mice, and CD94/NKG2A. Activating receptors include cytokine and chemokine receptors, and those that interact with ligands expressed on target cells, such as the natural cytotoxicity receptors or NCRs (NKp30, NKp44 and NKp46), NKG2D, CD244 and DNAM-1. In addition, NK cells express Fc?RIIIA or CD16, the receptor that exerts antibody-dependent cell mediated cytotoxicity (ADCC). NK cells also express the death ligands FasL and TRAIL. The killing or sparing of target cells depends on the integration of distinct signals that originate from NK cell receptors. NK cells spare healthy cells that express normal levels of MHC class I molecules and low amounts of stress-induced self-molecules, whereas they kill target cells that down-regulate MHC class I molecules and/or up-regulate stress-induced self-molecules. The latter are common signatures of virus-infected cells and tumors. All the accumulated knowledge on NK cell biology, along with many clinical observations, is driving multiple efforts to improve the arsenal of NK cell-based therapeutic tools in the fight against malignant diseases. Indeed, NK cell-based immunotherapy is becoming a promising approach for the treatment of many cancers. It is well known that NK cells have a significant role in the anti-tumor effect of therapeutic antibodies that use ADCC as a mechanism of action. In addition to this, administration of autologous and allogeneic NK cells after activation and expansion ex vivo is used in the treatment of cancer. Moreover, adoptive transfer of NK cell lines has been tested in humans, and genetically modified NK cells expressing chimeric antigen receptors are being studied in preclinical models for potential use in the clinic.

Toll-Like Receptor Activation in Immunity vs. Tolerance

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889196364 Year: Pages: 75 DOI: 10.3389/978-2-88919-636-4 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2016-04-07 11:22:02
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The innate immune system has evolved means to recognize and react suitably to foreign entities such as infectious agents. In many cases infectious microorganisms threaten the integrity and function of the target organs or tissues; therefore, consequent to their recognition the immune system becomes activated to ensure their elimination. Toll-like receptors (TLR) constitute a family of receptors specialized in the recognition of molecular patterns typically associated with infectious agents. Different TLRs exist, each selective for molecular entities and motifs belonging to a specific pathogen group. Consequently, it is thought that the molecular nature of invading microorganisms activates specific TLRs to drive adequate anti-infectious immunity. For instance, nucleic acid-specific, intracellular receptors (TLR3/7/8/9) are used to sense viruses and drive antiviral immunity, while other receptors (such as TLR2 and TLR4) recognize and promote immunity against bacteria, yeast, and fungi. Yet, it is becoming evident that activation of TLR pathways trigger mechanisms that not only stimulate but also regulate the immune system. For instance, TLR stimulation by viruses will drive antiviral interferon but also immunoregulatory cytokine production and regulatory T cell activation. Stimulation of TLRs by bacteria or using molecular agonists can also trigger both immune stimulatory and regulatory responses. TLR stimulation by infectious agents likely serves to activate but also control anti-infectious immunity, for instance prevent potential immunopathological tissue damage which can be caused by acute immune defense mechanisms. Previous work by us and others has shown that the immunoregulatory arm of TLR stimulation can additionally help control autoreactive processes in autoimmune disease. Hence, it is becoming established that gut commensals, which also play a crucial part in the control of autoimmune disease, establish immune regulatory mechanisms through activation of particular TLRs. In sum, it appears that TLRs are key immune players that not only stimulate but also regulate immune processes in health and disease. In this Research Topic, we wish to review the dual role of TLRs as activators and regulators of immune responses. We aim to motivate data-driven opinions as to the importance of context of TLR agonism for determining immune activation vs. regulation. The presentation of ongoing original works, as well as data and opinions around other innate immune receptors pertaining to this topic, are also encouraged.

Recent advances in γδ T cell biology: New ligands, new functions, and new translational perspectives

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889197842 Year: Pages: 269 DOI: 10.3389/978-2-88919-784-2 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-04-07 11:22:02
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Gamma/delta (γδ) T-cells are a small subset of T-lymphocytes in the peripheral circulation but constitute a major T-cell population at other anatomical localizations such as the epithelial tissues. In contrast to conventional a/ß T-cells, the available number of germline genes coding for T-cell receptor (TCR) variable elements of γδ T-cells is very small. Moreover, there is a prefential localization of γδ T-cells expressing given Vgamma and Vdelta genes in certain tissues. In humans, γδ T-cells expressing the Vg9Vd2-encoded TCR account for anywhere between 50 and >95% of peripheral blood γδ T-cells, whereas cells expressing non-Vd2 genes dominate in mucosal tissues. In mice, there is an ordered appearance of γδ T-cell „waves“ during embryonic development, resulting in preferential localization of γδ T-cells expressing distinct VgammaVdelta genes in the skin, the reproductive organs, or gut epithelia. The major function of γδ T-cells resides in local immunosurveillance and immune defense against infection and malignancy. This is supported by the identification of ligands that are selectively recognized by the γδ TCR. As an example, human Vgamma9Vdelta2 T-cells recognize phosphorylated metabolites („phosphoantigens“) that are secreted by many pathogens but can also be overproduced by tumor cells, providing a basis for a role of these γδ T-cells in both anti-infective and anti-tumor immunity. Similarly, the recognition of endothelial protein C receptor by human non-Vdelta2 γδ T-cells has recently been identified to provide a link for the role for such γδ T-cells in immunity against epithelial tumor cells and cytomegalovirus-infected endothelial cells. In addition to „classical“ functions such as cytokine production and cytotoxicity, recent studies suggest that subsets of γδ T-cells can exert additional functions such as regulatory activity and – quite surpisingly – „professional“ antigen-presenting capacity. It is currently not well known how this tremendous extent of functional plasticity is regulated and what is the extent of γδ TCR ligand diversity. Due to their non-MHC-restricted recognition of unusual stress-associated ligands, γδ T-cells have raised great interest as to their potential translational application in cell-based immunotherapy. Topics of this Research Focus include: Molecular insights into the activation and differentiation requirements of γδ T-cells, role of pyrophosphates and butyrophilin molecules for the activation of human γδ T-cells, role of γδ T-cells in tumor immunity and in other infectious and non-infectious diseases, and many others. We are most grateful to all colleagues who agreed to write a manuscript. Thanks to their contributions, this E-book presents an up-to-date overview on many facets of the still exciting γδ T-cells.

Oncolytic Viruses - Genetically Engineering the Future of Cancer Therapy

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889453580 Year: Pages: 193 DOI: 10.3389/978-2-88945-358-0 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Oncology --- Allergy and Immunology
Added to DOAB on : 2018-02-27 16:16:45
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The ability to genetically engineer oncolytic viruses in order to minimize side effects and improve the selective targeting of tumor cells has opened up novel opportunities for treating cancer. Understanding the mechanisms involved and the complex interaction between the viruses and the immune system will undoubtedly help guide the development of new strategies. Theranostic biomarkers to monitor these therapies in clinical trials serve an important need in this innovative field and demand further research.

Immunogenic Cell Death in Cancer: From Benchside Research to Bedside

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198382 Year: Pages: 145 DOI: 10.3389/978-2-88919-838-2 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Oncology
Added to DOAB on : 2017-02-07 16:12:31
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Classically, anti-cancer therapies have always been applied with the primary aim of tumor debulking achieved through widespread induction of cancer cell death. While the role of host immune system is frequently considered as host protective in various (antigen-bearing) pathologies or infections yet in case of cancer overtime it was proposed that the host immune system either plays no role in therapeutic efficacy or plays a limited role that is therapeutically unemployable. The concept that the immune system is dispensable for the efficacy of anticancer therapies lingered on for a substantial amount of time; not only because evidence supporting the claim that anti-cancer immunity played a role were mainly contradictory, but also largely because it was considered acceptable (and sometimes still is) to test anticancer therapies in immunodeficient mice (i.e. SCID/athymic mice lacking adaptive immune system). This latter practice played a detrimental role in appreciating the role of anticancer immunity in cancer therapy. This scenario is epitomized by the fact that for a long time the very existence of cancer-associated antigens or cancer-associated ‘danger signaling’ remained controversial. However, over last several years this dogmatic view has been considerably modified. The existence of cancer-associated antigens and ‘danger signaling’ has been proven to be incontrovertible. These developments have together paved way for the establishment of the attractive concept of “immunogenic cell death” (ICD). It has been established that a restricted class of chemotherapeutics/targeted therapeutics, radiotherapy, photodynamic therapy and certain oncolytic viruses can induce a form of cancer cell death called ICD which is accompanied by spatiotemporally defined emission of danger signals. These danger signals along with other factors help cancer cells undergoing ICD to activate host innate immune cells, which in turn activate T cell-based immunity that helps eradicate live (or residual) surviving cancer cells. The emergence of ICD has been marred by some controversy. ICD has been criticized to be either experimental model or setting-specific or mostly a concept based on rodent studies that may have very limited implications for clinical application. However, in recent times it has emerged (through mainly retrospective or prognostic studies) that ICD can work in various human clinical settings hinting towards clinical applicability of ICD. However a widespread consensus on this issue is still transitional. In the current Research Topic we aimed to organize and intensify a discussion that strives to bring together the academic and clinical research community in order to provide a background to the current state-of-the-art in ICD associated bench-side research and to initiate fruitful discussions on present and future prospects of ICD translating towards the clinical, bedside reality.

Immune Checkpoint Molecules and Cancer Immunotherapy

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457328 Year: Pages: 197 DOI: 10.3389/978-2-88945-732-8 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2019-01-23 14:53:43
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For the faultless function of the immune system, tight regulation of immune cell activation, immuno-suppression and the strength and efficiency of the immune response is essential. Immune checkpoint (ICP) molecules can amplify or dampen signals that lead to the modulation of specific immune activities. Under physiological conditions, immune checkpoints are essential to prevent autoimmune manifestations and to preserve self-tolerance. They help modulate immune responses by either promoting or inhibiting T-cell activation. However, in the context of cancer, malignant cells can dysregulate the expression of immune checkpoint proteins on immune cells in order to suppress anti-tumor immune responses and to gain immune resistance. Moreover, tumor cells themselves can also express some checkpoints proteins, thereby enabling these cells to externally orchestrate immune regulatory mechanisms. Several recent studies have confirmed that the expression of immune checkpoints could be an important prognostic parameter for cancer development and for patient outcome. Therefore, cancer immunotherapy based on the modulation of immune checkpoint molecules alone, or in combination with conventional tumor therapy (chemo- or/and radiotherapy), is now in focus as a means of developing new therapeutic strategies for different types of cancer. The two well-known molecules – CTLA4 and PD-1 - serve as important examples of such checkpoint proteins of important therapeutic potential. Thus far, inhibitors of CTLA4 and PD-1 have been approved to treat only a limited number of malignancies (e.g. malignant Melanoma, Non-Small Cell Lung Cancer). Many others are currently under investigation and the list of immune checkpoint molecules for potential therapeutic targeting is still growing. However, the clinical response to inhibitors of checkpoint molecules is not sufficient in all cases. Therefore, further studies are needed to improve our knowledge of such immunomodulatory proteins and their associated signaling pathways. Several key signaling pathways which are involved in the regulation of expression of checkpoint molecules in immune cells and in cancer cells have already been identified including MAPK, PI3K, NF-kB, JAKs and STATs. These (and future discovered) signaling pathways could give rise to the development of new strategies for modulating the expression of ICPs and thereby, improving anti-cancer immune responses. The main aim of the Research Topic is to collect novel findings from scientists involved in basic research on immune checkpoints as well as in translational studies investigating the use of checkpoint inhibtors in immunotherapy in experimental settings. We welcome the submission of Review, Mini-Review and Original Research articles that cover the following topics: 1. Molecular mechanisms underlying regulation of ICP expression in immune and/or cancer cells.2. Characterization of signaling pathways downstream ICP molecules.3. Cellular responses to ICP blockade.4. Identification of new compounds interfering with ICP expression and/or signaling.5. ICP-mediated interactions between cancer cells and immune cells. 6. Functional links between ICP and cytokines/chemokines.7. Molecular mechanisms of ICP inhibition in the context of experimental cancer immunotherapy.

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