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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.

New Therapies and Immunological Findings in Melanoma and Other Skin Cancers

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889457120 Year: Pages: 137 DOI: 10.3389/978-2-88945-712-0 Language: English
Publisher: Frontiers Media SA
Subject: Medicine (General) --- Allergy and Immunology --- Oncology
Added to DOAB on : 2019-01-23 14:53:43
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New therapies are currently being developed in the field of skin cancer. In particular, advances in melanoma now represent the frontline of cancer immunotherapy, as immunological findings in the disease have led to the development of highly effective immune-checkpoint inhibitors. However, these immune-checkpoint inhibitors are only effective in a subset of patients, and may not work in other skin cancer types, thus highlighting the need for further innovation in the field of skin cancer treatment.The purpose of this Research Topic is therefore to provide an up-to-date overview of immune processes and new therapies for melanoma and other skin cancers in order to further stimulate the development of new and even more successful treatments.

Control of Visceral Leishmaniasis by Immunotherapeutic and Prophylactic Strategies

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889195527 Year: Pages: 144 DOI: 10.3389/978-2-88919-552-7 Language: English
Publisher: Frontiers Media SA
Subject: Public Health --- Medicine (General) --- Allergy and Immunology
Added to DOAB on : 2016-01-19 14:05:46
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Visceral leishmaniasis (VL) or kala-azar is the most dreadful of all forms of leishmaniasis caused by Leishmania donovani in Old World and Leishmania chagasi and/or Leishmania infantum in New World affecting millions of people worldwide. In active VL, macrophages host the replicating amastigotes in phagolysosomal compartments leading to splenomegaly, hepatomegaly, hyperglobulinemia, anemia, weight-loss, incessant fever and ultimately death if not treated. Treatments available against the disease are limited by increased incidence of resistance, serious side-effects, high cost and long course of treatment. Immuno-chemotherapy is an alternative to overcome the limitations of the drugs against VL. Combination of one or more of immunotherapeutic agents like BCG, Alum, IFN-?, antigen-pulsed dendritic cells (DC), etc. with chemotherapeutic drugs have been tested raising hopes for a suitable immuno-chemotherapy against VL and Post Kala-azar Dermal Leishmaniasis (PKDL). Antagonists of IL-10, TGF-ß, IL-13 have been effectively used with pentavalent antimonials in treatment of experimental VL. Some parasitic antigens and liposomal formulations have also been shown to impart superior therapeutic effectiveness to antileishmanial drugs. For socio-economic reasons prophylaxis is always more desirable than therapy. Although no vaccine against any form of leishmaniasis in humans is available, patients successfully treated show considerable protection from reinfection highlighting the possibility of developing prophylactic measures against the disease. Subsequently a lot of interest has been focused recently towards developing vaccines against VL and many potential vaccine candidates like whole cell (attenuated or heat killed), crude fractions, purified subunits, DNAs, recombinant proteins, fusion proteins, and genetically modified live attenuated parasites etc. have been reported. These vaccine candidates are either activators of CD4+Th1 cells and/or CD8+ T cells or neutralizers of immuno-suppression. Cationic liposomal formulations, nanoparticle and virosome delivery systems, etc. have been used to increase potency and durability of various vaccine candidates. Immuno-modulators like TLR agonists have been shown to be promising adjuvants in enhancing efficacy and overcoming the challenge of human administrable vaccine formulations. Recently role of sand fly salivary gland proteins as immune-modulators also has been explored. Various strategies such as heterologous prime boosting, targeted antigen delivery, adjuvant mediated protection, have been undertaken. Likewise, precise role of regulatory T cells (Tregs) in VL disease progression needs to be investigated and exploited to develop both immuno-therapeutic and prophylactic methods. A breakthrough in immunotherapy and prophylactic strategy would help in eradication of the parasites from the pool of natural reservoirs namely VL and PKDL patients, asymptomatic carrier individuals and infected dogs ensuring success of global VL control programs.

Application of Antigen Cross-Presentation Research into Patient Care

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889451913 Year: Pages: 124 DOI: 10.3389/978-2-88945-191-3 Language: English
Publisher: Frontiers Media SA
Subject: Allergy and Immunology --- Medicine (General)
Added to DOAB on : 2017-10-13 14:57:01
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The activation of adaptive immune responses requires the processing and presentation of protein antigens to lymphocytes. Especially dendritic cells are effective at display of antigen-derived peptides in the form of immunogenic peptide/MHC complexes to CD4 and CD8-positive T cells, and can stimulate even naive T cells to clonally expand. During the last 40 years, mechanisms that facilitate antigen processing and presentation were clarified, mostly from work in cell lines and mouse models. From mouse-based work, it is now clear that dendritic cells represent a collection of specialized cell subsets that are particularly well endowed to stimulate antigen transport to distinct tissue locations, to transfer antigens between cellular subsets or to trigger T cell responses. Dendritic cell subsets hold great promise for therapeutic application, for example as dendritic cell-based vaccines to bolster immune responses against viruses or malignant growths. Hurdles remain that preclude the efficient application of high quality pre-clinical research into standardized patient care. In this research topic, efforts in dendritic cell research and dendritic cell-based vaccines are discussed, from both pre-clinical and application points of view.

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.

Biology-Driven Targeted Therapy of Pediatric Soft-Tissue and Bone Tumors: Current Opportunities and Future Challenges

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Book Series: Frontiers Research Topics ISSN: 16648714 ISBN: 9782889198191 Year: Pages: 147 DOI: 10.3389/978-2-88919-819-1 Language: English
Publisher: Frontiers Media SA
Subject: Oncology --- Medicine (General)
Added to DOAB on : 2016-01-19 14:05:46
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Recent advances in the understanding of the biological basis of pediatric soft-tissue and bone tumors, especially owing to the advent of “omics” technologies, have led to an exponential increase in the current knowledge on the genetic and cellular patho-mechanisms that drive these diseases. This offers the unprecedented opportunity to develop and implement targeted therapies such as monoclonal antibodies, small molecules, oncolytic viruses, and immunotherapies in standard and/or personalized treatment regimens. However, to date only a few examples document a successful translation of discoveries from the bench to the bedside. Recent international expert congresses such as the “Pediatric Cancer Translational Genomics” conference (Phoenix, Arizona, 2012), the ESF-EMBO workshop on “Molecular Biology and Innovative Therapies in Sarcomas” (Pultusk, Poland, 2012), and the AACR special meeting on “Pediatric Cancer at the Crossroads – Translating Discovery into Improved Outcomes” (San Diego, California, 2013) further emphasize the urgent need for a more rapid and especially more successful translational process. Hence, we strongly believe that a Frontiers Research Topic aiming at this aspect would fit just in time and that it would have great potential to receive numerous contributions of outstanding experts of the field. The proposed Frontiers Research Topic shall provide a platform for active and interdisciplinary discussion, summarize current state-of-the-art knowledge on all basic research and translational aspects in pediatric soft-tissue and bone tumors, and offer new perspectives of how to further promote and accelerate the translational process. We welcome high-quality original research articles, brief reports, as well as opinion, hypothesis, and review articles, and especially encourage submissions from early-career scientists.

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.

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