Immune Responses Against Tumors From The Bench To The Bedside

Traditionally, surgery, radiotherapy, chemotherapy and hormonal therapy have been used in clinical practice to treat cancer patients. However, these methods are either not completely tumor free or without collateral damage to health tissues. Therefore, tumor recurrence, partial remission, treatment side effect and poor tolerance in elderly patients, and lack of effective strategy to treat late-stage cancers have been the major hurdles faced by clinicians in health care. Although cancer immunotherapy including checkpoint blockade, CAR-T, oncolytic viruses, and recombinant cytokines has taken center stage in mainstream oncology because of its specifically targeting tumor cells without affecting surrounding normal cells, only a proportion of patients receiving treatment respond and others relapse after an initial response. Different tumor indications respond differently, and even in cancer types that respond, unresponsiveness are still observed. This resistance suggests that either lack of sufficient host recognition and immunity (intrinsic) or active immune suppression by tumor complex (acquired).

This translational, clinically oriented book describes in detail novel approaches to cancer immunotherapy, current strategies to target tumor immunosuppression, and prognostic biomarkers for personalized cancer treatments. Since the first, very successful edition of the book was published in 2015, the original chapters have been significantly updated and entirely new chapters are included on, for example, cancer immunoprevention, aptamer-mediated cancer gene therapy, haploidentical bone marrow transplantation for pediatric malignancies, and nanoimmunotherapy. The book is published as part of the three-volume Springer series Cancer Immunology, which aims to provide an up-to-date, clinically relevant review of cancer immunology and immunotherapy. Other volumes in the series address the translational medicine context and cancer immunotherapy for organ-specific tumors. Cancer Immunology: Bench to Bedside Immunotherapy of Cancers will be of special value to clinical immunologists, hematologists, and oncologists.

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.

The immune system offers the possibility of treating cancer and its metastasis without the toxicities of chemotherapy. Unfortunately, despite recent medical advances, overall survival of patients is still relatively dismal. Advances such development of Provenge, which is the first widely accepted immunotherapy of cancer have attracted media attention and interest, however survival advantage was only 3 months in double blind trials. In this book we take a multi-disciplinary approach to analyzing in a highly referenced and technical manner the various cellular, biochemical and immunological changes that occur in cancer patients. By categorizing what cancer does to the body, and how the body tries to fight the cancer, an overall picture is painted of various interventions and combination interventions that can be tried in order to maximize probability of patient improvement. Various conventional and unconventional approaches to cancer are described in this volume, including macrophage activation therapy, oxidative medicine, lymphokine activated killers, and non-specific immune stimulants. Significant effort was made by the authors to detail how various components of the immune system collaborate in the recognition of cancer cells, how cancer cells avoid immune attack, and means of derepressing immunity using chemical, cellular, and genetic approaches. Specific tumor immune evasion mechanisms that are described include: a) the tryptophan-catabolizing enzyme indolamine 2,3 deoxygenase (IDO), which selectively induces suppression of cytotoxic T cells through anergy, apoptosis, and T regulatory cell generation; b) IL-10, a cytokine produced by tumor cells, as well as tumor-associated macrophages, which induces generation of T regulatory cells; c) cancer derived exosomes, which act as nanoparticle vesicles, that directly induce apoptosis of tumor-reactive T cells, as well as assist in formation of extracellular matrix that is receptive to tumor metastasis; d) soluble HLA-like molecules including MICA, which block the activation of natural killer cells, the cells that are capable of killing tumors which have downregulated antigen presentation; e) arginase, an enzyme produced by M2 macrophages, which produces an immune suppressive localized environment; and f) tumor lactic acid accumulation, which blocks cytotoxic activity of T cells, while at the same time allowing for survival of T regulatory cells, which in turn suppress the immune system. In addition to overviewing how cancer suppresses the immune system, discuss how the immune system suppresses cancer. Detailed descriptions are provided of immune modulators that have demonstrated clinical efficacy signals dating back from the days of Coley's toxins, all the way to the current immune checkpoint inhibitor trials. Specific areas of concentration include: a) cytokine induced killer cells; b) lymphokine activated killers; c) BCG; and d) cancer vaccines. We trust that the current volume will provide its readers not only with details of the immune-tumor interaction, but will also provide solid support for novel experimental approaches to cancer, including combination of T regulatory cell depleting chemotherapies with immunotherapy, as well as combinations of intravenous nutrients with immune stimulators.

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.

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.

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.

Biomaterials have existed for millennia as mechanical replacement structures following disease or injury. Biomaterial design has changed markedly from structural support with an “inert immune profile as the primary objective to designs that elicit an integrative local tissue response and a pro-repair immune cell phenotype. Immunomodulatory Biomaterials: Regulating the Immune Response with Biomaterials to Affect Clinical Outcome offers a single, comprehensive reference on biomaterials for modulation of the host response, for materials scientists, tissue engineers and those working in regenerative medicine. This book details methods, materials and strategies designed to regulate the host immune response following surgical implantation and thus facilitate specific local cell infiltration and tissue deposition. There has been a dramatic transformation in our understanding of the role of the immune system, both innate and adaptive; these changes include recognition of the plasticity of immune cells, especially macrophages, cross-talk between the immune system and stem cells, and the necessity for in situ transition between inflammatory and regulatory immune cell phenotypes. The exploitation of these findings and the design and manufacture of new biomaterials is occurring at an astounding pace. There is currently no book directed at the interdisciplinary principles guiding the design, manufacture, testing, and clinical translation of biomaterials that proactively regulate the host tissue immune response. The challenge for academia, industry, and regulatory agencies to encourage innovation while assuring safety and maximizing efficacy has never been greater. Given the highly interdisciplinary requirements for the design, manufacture and use of immunomodulatory biomaterials, this book will prove a useful single resource across disciplines. Holistically covers the design, manufacture, testing, and clinical translation of biomaterials that proactively regulate the host tissue immune response Provides a single reference for understanding and utilizing the host response in biomaterials design An international collaboration of leading researchers in the field offering a novel insight into this fast-growing area

Topic Editor Dr. Lewis Shi received financial support from Varian Medical System, Inc. The other Topic Editors declare no competing interests with regard to the Research Topic subject.

Topic Editor Prof. Aimin Xu receives financial support from Servier Laboratories. The other Topic Editors declare no competing interests with regards to the Research Topic theme.