CD4+FoxP3+ regulatory T cells (Tregs) play an indispensable role in the maintenance of immune homeostasis and prevention of autoimmune diseases, and represent a major cellular mechanism of tumor immune evasion. Targeting of Tregs has great potential in the treatment of some major human diseases, including autoimmunity, transplant rejection, GvHD, and cancer, and are critical controllers of immunity to infectious pathogens. It is expected they will also be central to the control of allergic and inflammatory diseases. Understanding the biological pathways crucial for the regulation of Treg activity is a prerequisite for harnessing the immense therapeutic potential of Tregs. TNF is generally believed to be a master pro-inflammatory cytokine, and anti-TNF therapy has become a mainstay treatment for some autoimmune diseases. However, experimental evidence indicates that TNF preferentially activates Tregs, resulting in the expansive proliferation, phenotypic stability, and enhanced suppressive capacity of these immune suppressors. This effect of TNF is mediated by TNFR2, which is preferentially expressed by human and mouse Tregs. Furthermore, expression of TNFR2 is able to identify the most suppressive subset of Tregs. Although counterintuitive and contradictory to earlier reports, these findings have been supported by increasing experimental evidence from both human and mouse studies. These recent studies revealing the Treg-promoting effect of TNF not only leads to the redefinition of the immunological biology of this pleiotropic cytokine, they are also helpful in designing novel therapies in the treatment of cancer, autoimmune diseases, and GvHD, as well as enhancing current vaccines and immunomodulators. In this article collection, current knowledge on the cellular and molecular aspects of the Treg-stimulatory effect of the TNF-TNFR2 pathway will be discussed. An insight of the physiological and pathological roles of such effects of TNF in an inflammatory reaction and immune response will be provided. The seemingly contradictory Treg-promoting effect of TNF and immunosuppressive effect of anti-TNF therapy will be analyzed. Recent efforts to translate such discoveries into therapeutic benefits will be introduced. The novel strategies in the treatment of cancer and GvHD, by down- or up-regulation of Treg activity through targeting TNFR2, will be highlighted. In addition to Tregs, TNFR2 has also been found to play a key role in the accumulation and immunosuppressive function of myeloid-derived suppressive cells (MDSCs) and Mesenchymal stem cells (MSCs). Therefore, the current understanding of the role of TNF-TNFR2 signal in other type of immunosuppressive cells, as well as its clinical and therapeutic implications, have also been considered.

Diffuse Large B Cell Lymphoma (DLBCL) is the most common Non-Hodgkin Lymphoma in Western countries and is comprised of a heterogeneous group of biologically distinct entities resulting in the clonal proliferation of a germinal or post-germinal malignant B cell. The disease is particularly aggressive with 40% of the afflicted individuals succumbing to the disease. The standard treatment for DLBCL is still chemo-immunotherapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Whilst this modality is safe and effective, up to 45%–50% of patients will relapse. Despite advances in therapy, DLBCL remains a challenging disease to manage, with significant heterogeneity in clinical presentation and outcomes. Therefore, there is a need to update the medical community with the latest updates in the diagnosis and treatment of DLBCL.

This book addresses one of the major challenges of immunology today that is being directed to the translation of the rapidly emerging volume of basic science contributions of immunology to clinical medicine. In so doing, the book systemically introduces and discusses concepts, classifications, phenotypic and functional descriptions of regulatory T (Treg) cells in health and disease. The authors of the 15 chapters were selected from among the most qualified experts in the field of Treg cell research who provide a comprehensive overview of Treg cells and their biology in the ensuing chapters. The beginning chapters provide a useful contemporary classification of Treg cell populations and then progress to chapters that explore basic mechanisms of Treg cell function and epigenetic control. In addition to descriptions of typical CD4+ Foxp3+ cells, other chapters provide detailed presentations of Treg subsets such as CD8+ Tregs and IL-10-producing Tr1 cells. The differences of various Treg subsets, as well as circulating and resident Treg cell populations, are next compared. Importantly, the next chapters provide the clinical correlation of Treg cells with autoimmune diseases, inflammatory diseases, metabolic diseases, cancer and organ transplantation and progress to chapters that highlight emerging innovative technology including nanoparticle-Treg cells and their translational values. In summary, the book will provide a valuable resource not only for graduate students and researchers in the fields of immunology, cell biology and translational medicine but also for all others interested in learning more about Treg cells and their application in human health and disease.

The receptors of the TNFRSF (TNFRs) are of overwhelming importance in the regulation of the immune system but are also involved in the induction of apoptotic cell death or cell survival and proliferation, making them excellent therapeutic targets for cancer but also other diseases. TNFRSF members provide crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFR has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. For example, the two receptors of TNF, TNF receptor-1 (TNFR1) and TNF receptor-2 (TNFR2), regulate the interaction of the various types of immune cells and also the interplay of the latter with practically any type of non-hematopoietic cells; CD40 stimulates antigen-presenting cells; CD27, OX40, 41BB,GITR, HVEM and RANK costimulate T cells; BCMA, TACI, and BaffR regulate B-cell maturation; CD95 and the two death receptors of TRAIL contribute to tumor surveillance and Fn14, EDAR and XEDAR have been implicated in tissue regeneration and development. Correspondingly, exploiting TNFR-mediated signaling for the therapy of cancer but also of non-cancerous diseases is a major field of interest. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF receptor into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. The goal of this research topic is to provide concise overview of the recent advances in our understanding of agonists targeting TNFRSF and their potential therapeutic use, in particular in cancers. The focus of the series of research and review articles includes but is not limited to the biology of TNFRSF receptors in distinct immune cell populations, structure-function relationship of TNFRSF agonists, current preclinical and clinical knowledge of co-stimulatory TNFR agonists, opportunities for next generation TNFRSF therapeutics alone or in combination with immune checkpoint molecules. We encourage the submission of original research articles supported by pre-clinical data. Review articles will also be considered. Data should consist of anti-tumor activity analyses encompassing various murine or humanized mouse models, assessment of TNFRSF targeting in translational ex vivo primary human tumor tissue settings, or innovative single cell or spatial analysis of TNFRSF expression and association with tumor progression in patient material. Submissions should not be limited to the in vitro evaluation of TNFRSF signaling. We expect submissions based on (but not limited to): • TNFRSF signaling in shaping the immune contexture for anti-tumor immunity. • Engaging cytotoxic TNFRSF signaling to treat cancer. • Engaging TNFRSF signaling in non-cancerous diseases. • Immunobiology of TNFRSF receptors in specific immune cell populations, eg regulatory T cells (TNFR2, 41BB, TNFRSF25, ..), dendritic cells (CD40, RANK …), NK cells … • Critical aspects of TNFRSF structure-function and receptor clustering . • Balancing agonistic strength with FcγR affinity in the context of opportunities for next generation anti-TNFR antibodies with improved pharmacologic properties. • TNFSF-based agonists with conditional or constitutive agonism. • Potential of simultaneous blockade of immune checkpoint molecules and co-stimulation of the TNFRSF in improving anti-tumor immunity. • Bispecific TNFR agonists. • anti-TNF-α agents in cancer immunotherapy. • Prominence and key features of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) as co-stimulatory domains in CAR-T cell therapy . • Current preclinical and clinical knowledge of co-stimulatory TNFR antibodies. Topic Editor Nataša Obermajer is a full time employee and shareholder of Janssen R&D, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Topic Editor Dr. Adam Zwolak is employed by Janssen R&D; The University of Würzburg has filed patent applications for TNFR2, Fn14 and CD40 agonists and bispecific anti-TNFR antibody formats with conditional activity with Dr. Harald Wajant as co-inventor. The University of Würzburg receives funding from Dualyx NV for the development of TNFR2 agonists

During the past decades, with the introduction of the recombinant DNA, hybridoma and transgenic technologies there has been an exponential evolution in understanding the pathogenesis, diagnosis and treatment of a large number of human diseases. The technologies are evident with the development of cytokines and monoclonal antibodies as therapeutic agents and the techniques used in gene therapy. Immunopharmacology is that area of biomedical sciences where immunology, pharmacology and pathology overlap. It concerns the pharmacological approach to the immune response in physiological as well as pathological events. This goals and objectives of this textbook are to emphasize the developments in immunology and pharmacology as they relate to the modulation of immune response. The information includes the pharmacology of cytokines, monoclonal antibodies, mechanism of action of immune-suppressive agents and their relevance in tissue transplantation, therapeutic strategies for the treatment of AIDS and the techniques employed in gene therapy. The book is intended for health care professional students and graduate students in pharmacology and immunology.