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The field of cancer immunotherapy has been transformed over the last decade, with a significant emphasis on T cell-based therapies due to their ability to attack cancer cells specifically. However, despite substantial progress in the development of T cell-based cancer immunotherapies, a large proportion of patients do not respond favorably, particularly in 'cold' tumors, which are typically categorized by a lack of tumor antigens, and defective antigen-presenting cell (APC) and T cell priming, activation, or infiltration. Methods for characterizing and modulating tumor microenvironments (TME) could help develop future immunotherapies. The current thesis investigates two avenues of research: developing new methods for detecting tumor antigens and developing novel therapeutics to make tumors 'hot' and boost anticancer immunity. The first project focuses on discovering class I major histocompatibility complex (MHC-I)-bound tumor antigens that govern the specificity and activation of CD8+ T cells. Traditional methods using mass spectrometry (LC-MS/MS) based MHC-peptide identification suffer from inflated search spaces, leading to limited efficiency and poor statistical power in peptide mapping and identification. The current thesis addresses these shortcomings by employing a targeted database search strategy and developing an accompanying tool, SpectMHC, which is based on previously predicted MHC-I peptides. This unique technique improved the identification rates and statistical power of MHC-I peptides in human and mouse models in an MS-based peptide discovery platform. The later projects focus on utilizing immunogenic cell death (ICD) of cancer, a regulatory form of cell death characterized by enhanced antigenicity and adjuvanticity, to modulate the TME and initiate specific anticancer immune responses mediated by APCs and T cells. We created novel photodynamic therapies that target cancer cells directly via cytotoxic and indirectly via inflammatory responses, induction of the hallmarks of ICD, and activation of dendritic cells resulting in protective anticancer immunity. This research resulted in the development of promising immunogenic photodynamic therapies for the treatment of melanoma, which have the potential to be translated from bench to bedside. Overall, the current thesis presents novel strategies for understanding and inducing T cell-mediated anticancer immune responses.
Delivery Technologies for Immuno-Oncology: Volume 1: Delivery Strategies and Engineering Technologies in Cancer Immunotherapy examines the challenges of delivering immuno-oncology therapies. Immuno-oncology (IO) is a growing field of medicine at the interface of immunology and cancer biology leading to development of novel therapeutic approaches, such as chimeric antigen receptor T-cell (CAR-T) and immune checkpoint blockade antibodies, that are clinically approved approaches for cancer therapy. Although currently approved IO approaches have shown tremendous promise for select types of cancers, broad application of IO strategies could even further improve the clinical success, especially for diseases such as pancreatic cancer, brain tumors where the success of IO so far has been limited. Nanotechnology-based targeted delivery strategies could improve the delivery efficiency of IO agents as well as provide additional avenues for novel therapeutic and vaccination strategies. Additionally, a number of locally-administered immunogenic scaffolds and therapeutic strategies, such as the use of STING agonist, could benefit from rationally designed biomaterials and delivery approaches. Delivery Technologies for Immuno-Oncology: Volume 1: Delivery Strategies and Engineering Technologies in Cancer Immunotherapy creates a comprehensive treaty that engages the scientific and medical community who are involved in the challenges of immunology, cancer biology, and therapeutics with possible solutions from the nanotechnology and drug delivery side. Comprehensive treaty covering all aspects of immuno-oncology (IO) Novel strategies for delivery of IO therapeutics and vaccines Forecasting on the future of nanotechnology and drug delivery for IO
Active specific immunotherapy is a promising but investigational modality in the management of cancer patients. Currently, several different cancer vaccine formulations such as peptides, proteins, antigen-pulsed dendritic cells, whole tumor cells, etc. in combination with various adjuvants and carriers are being evaluated in clinical trials (1-3). To determine the optimal cancer vaccine strategy, a surrogate immunological end-point that correlates with clinical outcome needs to be defined, since it would facilitate the rapid comparison of these various formulations. Traditional immunological assays such as ELISA, proliferation and cytotoxicity assays can detect immune responses in vaccinated patients but are not quantitative. In contrast, novel assays such as enzyme-linked immunospot (ELISPOT) assay, intracellular cytokine assay and tetramer assay can quantitate the frequency of antigen-specific T cells. Of these, the ELISPOT assay has the 5 lowest detection limit with 1/10 peripheral blood mononuclear cells (PBMC) and has been determined to be one of the most useful assays to evaluate immune response to cancer vaccines (4). However, the IFN-? ELISPOT assay is not an exclusive measure of cytotoxic T-lymphocyte (CTL) activity as non-cytotoxic cells can also secrete IFN-?. Additionally, CTL with lytic activity do not always secrete IFN-? (5). A more relevant approach to assess functional activity of cytotoxic lymphocytes would be to measure the secretion of molecules that are associated with lytic activity. One of the major mechanisms of cell-mediated cytotoxicity involves exocytosis of cytoplasmic granules from the effector toward the target cell.
Leading investigators and clinicians detail the different mechanisms used by tumors to escape and impair the immune system and then spell out possible clinical strategies to prevent or reverse tumor-induced immune dysfunction. The authors review the mechanisms of immune dysfunction and evasion mechanisms in histologically diverse human tumors, focusing on tumor-induced molecular defects in T cells and antigen-presenting cells (dendritic cells and tumors), that may serve as biomarkers for patient prognosis. They discuss the means by which these immune functions may be protected or restored in order to more effectively support the process of tumor rejection in situ. Cutting-edge techniques are outlined with the capacity to monitor the strength and quality of patients' immune responses using immunocytometry, MHC-peptide tetramers combined with apoptosis assay, ELISPOT assay, and detection of MHC-TAA peptide complexes on tumor cells.
The complex interactions between the innate and adaptive immune systems function to recognize and clear pathogens or transformed cells, but inefficient interactions between these two systems can result in harmful immunologic responses including chronic infections and the development of cancer. Several hallmarks of dysfunctional adaptive immune responses often detected in tumors share specific features with ineffective immunity in chronic infections. The members of the micromilieu actively participate in the process of tumorigenesis or chronification of infection by modulating innate and adaptive immune system interactions leading e.g. to insufficient T cell responses. The best example is given by the acquisition of an “exhausted” state of cytotoxic CD8+ T cells (CTLs) responding to chronic infections or tumors that are associated with elevated expression of inhibitory receptors and impaired cytokine response. Targeting these major inhibitory pathways by immune checkpoint blockers represents a prime example of successful clinical translation of tumor-specific immunotherapies. Understanding the mechanisms behind (mal)adaptations of the immune system is crucial for achieving therapeutic benefits. The establishment and co-evolution of a dynamic microenvironment niche constituted by the recruitment of numerous cell types dampen immune responses and thus contribute to the development of neoplastic transformation as well as infection. Although there are examples of successful immunotherapeutic approaches (CAR-T cells, immune checkpoint inhibitors, or mRNA vaccination), a large percentage of patients with cancer or chronic infections still do not benefit from these therapies or develop severe immune-related adverse events. The reasons for these failures are not well understood. A possible explanation might be that current immunotherapies target predominantly the effector arm of the immune system by trying to reactivate dysfunctional T cells, but do not sufficiently address the influence of the innate immune system and the contributions of the tumor microenvironment (TME) niche. The main problem we would like to address in this special issue is how inappropriate function of the innate immune system affects adaptive immunity and contributes to inefficient anti-cancer immunity and chronification of infections. The central goal is to provide a more precise understanding of the various (common and novel) immune evasion mechanisms in cancers and in chronic infections to obtain a detailed map of common and disease-specific immune escape checkpoints. To that aim, we want to compile a wide array of interdisciplinary studies exploring a comparative and multi-layered analysis of mechanisms responsible for inefficient immune responses, including novel approaches i.e. multi-omics or epigenetic signaling. We would also like to combine studies from different fields, including basic and clinical immunology, oncology, and virology/microbiology. We welcome the submission of Original Research, Review, Mini-Review, Methods, Case report, and Perspective articles that cover, but are not limited to the following topics: • Convergent mechanisms supporting immune escape in preclinical models (tumors and chronic infections) • Convergent evasion mechanisms mediated by tumor-infiltrating suppressive cells (Treg, MDSC, macro-phages, soluble mediators, signaling, metabolism, ...) • Convergent immune evasion mechanisms mediated by chronic infection (viral or parasite) • Novel strategies to modulate the TME by direct or indirect targeting of immune suppressor cells. • Approaches to enhance persistence and resilience of anticancer T cells • Combinatorial therapeutic strategies (mRNA, antibodies, immune checkpoint blockers …) that target convergent immune evasion mechanisms Manuscripts consisting solely of bioinformatics or computational analysis of public genomic or transcriptomic databases which are not accompanied by robust and relevant validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this topic.
Once alerted by the innate immune system to the presence of a pathogen or a cellular abnormality, the adaptive immune system responds by activating and expanding antigen-specific B and T lymphocytes. This chapter focuses specifically on the activation and activities of T lymphocytes, which coordinate the adaptive immune response. We open with a description of where and how naïve T cells first encounter antigen. We then examine what factors influence the differentiation of helper CD4+ T lymphocytes into one of several effector subsets, each of which secretes a distinct subset of cytokines. We follow with a discussion of the origin and function of cytotoxic CD8+ T cells, the lymphocyte with the capacity to directly kill tumor cells. We close with a brief summary of the unique challenges that face the adaptive immune system when it tried to mount a response to a tumor.
This book will cover primary roles of NKT cells in immunity to cancer, in both mouse tumor models and cancer patients. There are several chapters describing general aspects of NKT cells.
The brief description of tumours being “wounds that do not heal” by Dr Harold F. Dworak nearly three decades ago (N Engl J Med 1986) has provided not only a vivid illustration of neoplastic diseases in general but also, in retrospect conceptually, a plausible immunological definition of cancers. Based on our current understanding in the field, it could have even a multi-dimensional meaning attached with. This relates to several important issues which need to be addressed further, i.e. in terms of a close link between chronic inflammation and tumourigenesis widely observed; clinical and experimental evidence of immunity against tumours versus the highly immunosuppressive tumour microenvironment being associated; and their underlying immunological mechanisms, oncogenic basis, as well as the true causal relationship in question. Recent findings from studies into the pathogenesis of autoimmunity and, more importantly, the mechanisms which protect against it, have offered some new insights for our understanding in this direction. Chronic or persistent autoimmune-like inflammatory conditions are evidently associated with tumor development. The important question is about their true causal relationship. Chronic or persistent inflammation has been shown to contribute directly to tumour development by triggering neoplastic transformation and production of inflammatory mediators which could promote cancer cell survival, proliferation and invasion. On the other hand, tumours are mutated self-tissue cells to which the host immune system is largely tolerized otherwise. Although the mutations may give rise to the expression of tumour-specific antigens (TSA) or tumour-associated antigens (TAA), most of these TSAs/TAAs are found to be poor immunogens. The ongoing inflammatory conditions may therefore reflect a desperate attempt of the host immune system to mount anti-tumour responses, though ineffectively, being a consequence of the continuous yet largely futile triggering by those poorly immunogenic TSAs/TAAs. Furthermore, during autoimmune or overtly persistent immunological responses, many regulatory mechanisms are triggered in the host in attempts to limit the ongoing harmful inflammatory reactions. Such a negative feedback regulation is known to be crucial in preventing normal individuals from immune-mediated diseases. As a result of the negative feedback loop, however, an excessive production of anti-inflammatory or immunosuppressive molecules followed by the exhaustion of the immune effector cells may instead lower the ability of the host immune system to mount specific anti-tumor responses, allowing the escape of tumour or mutated cells from immunosurveillance. This may also help to explain why the most effective way to enhance host immunity against cancer is by targeting the negative arm of immune regulation. In this Frontiers Research Topic, we aim to gather current views from experts in these inherent overlapping fields of oncology, autoimmunity and tumour immunology, and to make them available to our potential readership who may be particularly interested in this cutting-edge area. By understanding how the immune system is normally regulated, why dysregulation of which may cause the immunological-oncological related diseases, we also encourage further discussions as to how the so-called "self-reactivity" (autoimmune responses) can be alternatively switched on and redirected, immunologically or molecularly, for effective cancer treatment.
Innate and adaptive immunity play important roles in immunosurveillance and tumor destruction. However, increasing evidence suggests that tumor-infiltrating immune cells may have a dual function: inhibiting or promoting tumor growth and progression. Although regulatory T (Treg) cells induce immune tolerance by suppressing host immune responses against self- or non self-antigens, thus playing critical roles in preventing autoimmune diseases, they might inhibit antitumor immunity and promote tumor growth. Recent studies demonstrate that elevated proportions of Treg cells are present in various types of cancers and suppress antitumor immunity. Furthermore, tumor-specific Treg cells can inhibit immune responses only when they are exposed to antigens presented by tumor cells. Therefore, Treg cells at tumor sites have detrimental effects on immunotherapy directed to cancer.
This volume explores the various methods used to study tertiary lymphoid structures (TLS) in pathological situations. Pre-clinical models are also discussed in detail to show how TLS structure, development, and maintenance can be targeted and studied in vivo. The chapters in this book cover topics such as humans and mice; strategies to quantify TLS in order to use it in stained tissue sections; classifying a gene signature form fixed and paraffin-embedded tissues; and development of murine inflammatory models to help look at TLS in the context of infection or malignancy. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and tips on troubleshooting and avoiding known pitfalls. Authoritative and thorough, Tertiary Lymphoid Structures: Methods and Protocols is a valuable resource that increases the reader’s knowledge on immune functions and how they will pave the way to future therapeutic applications.