Immune Metabolism In Health And Tumor

This book offers a broad overview of the concepts and research findings in immunometabolism. The immune system is made up of numerous different cell types, pathways, and components that must be able to respond rapidly to a pathogen or cancer, but must also remain quiescent in the absence of challenges. Immune cells rely on metabolic pathways to adapt to changing environments and stimuli. Additionally, these cells can be modified in function or fate by fluctuations in available nutrients. The chapters in this book describe ways in which immune cells utilize and are regulated by metabolic pathways. Topics include how immune-cell metabolism shapes immune homeostasis, and how dysregulation of these pathways can lead to immune disorders. In different contexts, such as a tumor microenvironment, immune-cell function and identity may be modified not only by cytokines and checkpoint molecules, but also by nutrient availability and other metabolic stimuli. Transcriptional reprogramming confers many of the changes in immune cell metabolism that are seen when a T-cell, for example, undergoes activation or functional adaptation to different environments. Lastly, immune cells can destructively or protectively participate in human metabolic homeostasis or disorders. This book summarizes immune-metabolism from a variety of different perspectives, including the ways in which metabolic cues, pathways, and requirements of immune cells change in conditions of homeostasis and activation. The exploration of the significance of metabolic checkpoints and other cues, particularly in the context of cancer and immune disorders, may form the foundation for the development of therapeutics.

Metabolism of glucose, lipids, amino acids, and nucleotides represents the fundamental capability of host to utilize distinct nutrients and energy to support diverse function of different cell lineages. Cancer cells undergo the Warburg Effect to adapt to the microenvironment composed by stromal cells and immune cells. The crosstalk among cancer cells and immune cells orchestrate tumor progression. In the tumor microenvironment, immune cells also show metabolic reprogramming. For example, naive or memory T cells switch from the oxidation of fatty acids to glycolysis and glutaminolysis after activation; meanwhile massive glucose and glutamine are transported into cells to meet their metabolic demands. Defective glucose or glutamine metabolism impairs the differentiation and expansion of helper T cells. The molecular pathways that control immune cell metabolism and function are intimately linked. Understanding such metabolic reprogramming of immune cells in the tumor microenvironment could offer new directions in manipulation of peripheral immune responses. Recent findings in immune cell metabolism hold the promising possibilities by metabolic manipulation of immune cells towards clinical therapeutics for treating cancer. This Research Topic includes updated findings and views in the metabolism of cancer cells and immune cells in the tumor microenvironment.

Genetic alterations in cancer, in addition to being the fundamental drivers of tumorigenesis, can give rise to a variety of metabolic adaptations that allow cancer cells to survive and proliferate in diverse tumor microenvironments. This metabolic flexibility is different from normal cellular metabolic processes and leads to heterogeneity in cancer metabolism within the same cancer type or even within the same tumor. In this book, we delve into the complexity and diversity of cancer metabolism, and highlight how understanding the heterogeneity of cancer metabolism is fundamental to the development of effective metabolism-based therapeutic strategies. Deciphering how cancer cells utilize various nutrient resources will enable clinicians and researchers to pair specific chemotherapeutic agents with patients who are most likely to respond with positive outcomes, allowing for more cost-effective and personalized cancer therapeutic strategies.

This book discusses the novel metabolic cross-talk between immune and tumor cells in the tumor microenvironment that promotes their growth and progression. It also describes deregulated metabolism in cancer cells that promotes suppressive and cancer cell-favourable microenvironment. Further, the book provides novel insights on the metabolic changes in immune cells that promote tumor cell growth and survival. In turn, it also reviews the involvement of immuno-onco metabolic cross-talk in the development of resistance to chemo-radiation therapy (CRT) in tumor cells. Lastly, it also explores the potential of immuno-oncology metabolism as a therapeutic approach against tumor cells.

Obesity and its co-morbidities, including atherosclerosis, insulin resistance and diabetes, are a world-wide epidemic. Inflammatory immune responses in metabolic tissues have emerged as a universal feature of these metabolic disorders. While initial work highlighted the contribution of macrophages to tissue inflammation and insulin resistance, recent studies demonstrate that cells of the adaptive immune compartment, including T and B lymphocytes and dendritic cells also participate in obesity-induced pathogenesis of these conditions. However, the molecular and cellular pathways by which the innate and adaptive branches of immunity control tissue and systemic metabolism remain poorly understood. To engage in growth and activation, cells need to increase their biomass and replicate their genome. This process presents a substantial bioenergetic challenge: growing and activated cells must increase ATP production and acquire or synthesize raw materials, including lipids, proteins and nucleic acids. To do so, they actively reprogram their intracellular metabolism from catabolic mitochondrial oxidative phosphorylation to glycolysis and other anabolic pathways. This metabolic reprogramming is under the control of specific signal transduction pathways whose underlying molecular mechanisms and relevance to physiology and disease are subject of considerable current interest and under intense study. Recent reports have elucidated the physiological role of metabolic reprogramming in macrophage and T cell activation and differentiation, B- and dendritic cell biology, as well as in the crosstalk of immune cells with endothelial and stem cells. It is also becoming increasingly evident that alterations of metabolic pathways play a major role in the pathogenesis of chronic inflammatory disorders. Due to the scientific distance between immunologists and experts in metabolism (e.g., clinicians and biochemists), however, there has been limited cross-talk between these communities. This collection of articles aims at promoting such cross-talk and accelerating discoveries in the emerging field of immunometabolism.

Immunometabolism has emerged as an intersectional crossroad between metabolism and immune response. Over the past decade, it has become clear that most - if not all - immune cell functions are not separated from cellular metabolism. Although seminal works have addressed the metabolic fate of immune cells during differentiation and function, the physiological status of a given tissue is also dependent on the cell metabolism. The dialogue between immune cells and their microenvironment can also modulate cellular metabolism, which can trigger the onset and progression of a multitude of inflammation-mediated diseases. Thus, uncovering the specific characteristics of the metabolism in different immune cells types and in different conditions, can shed light into the molecular mechanisms of disease and help develop new drugs and therapeutic strategies to treat immune diseases. The edited volume Essentials aspects of Immunometabolism will give the readers a broad view on how metabolic pathways can influence many types of immune cells during activation, differentiation and function, in health and disease. Of note, the structure of the book was created thinking not only on the experienced immunologist but also on undergraduate and graduate students, physicians, and all members of the scientific community interested in this exciting field of research.

We acknowledge the initiation and support of this Research Topic by the International Union of Immunological Societies (IUIS). We hereby state publicly that the IUIS has had no editorial input in articles included in this Research Topic, thus ensuring that all aspects of this Research Topic are evaluated objectively, unbiased by any specific policy or opinion of the IUIS.

The book addresses controversies related to the origins of cancer and provides solutions to cancer management and prevention. It expands upon Otto Warburg's well-known theory that all cancer is a disease of energy metabolism. However, Warburg did not link his theory to the "hallmarks of cancer" and thus his theory was discredited. This book aims to provide evidence, through case studies, that cancer is primarily a metabolic disease requring metabolic solutions for its management and prevention. Support for this position is derived from critical assessment of current cancer theories. Brain cancer case studies are presented as a proof of principle for metabolic solutions to disease management, but similarities are drawn to other types of cancer, including breast and colon, due to the same cellular mutations that they demonstrate.

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).

Historically the study of the immune system and metabolism have been two very separate fields. In recent years, a growing literature has emerged illustrating how the multiple processes of cellular metabolism are intricately linked to several aspects of immune function and development. This Research Topic covers recent progress in the field now known as “Immunometabolism” and the role of metabolism in immune tolerance. Immune tolerance is operationally defined as a state where a host’s immune system is balanced such that although self-reactive lymphocytes are present, they are kept in check by immune regulation. Perturbations to this homeostasis may result in self-reactive lymphocytes gaining the upper hand and mediating auto-immune disease. Maintenance of immune tolerance involves a large cast of different cell types including effector T cells, regulatory T cells, B cells, stromal cells, dendritic cells and macrophages. Intracellular pathways and individual enzymes of metabolism have been shown to be harnessed by cells of both the adaptive and innate immune system to allow particular immune functions to be achieved. Examples include metabolic enzymes serving ‘moonlighting’ functions in mRNA translation, gene splicing, and kinase activation. Other examples include the requirement for de novo fatty acid synthesis for differentiation into Th17 effectors and CD8 memory T cells or products of the TCA cycle promoting pro-inflammatory cytokine production. Likewise, the availability of extracellular metabolic substrates has a large impact on the maintenance of local immune tolerance. For example, there are different requirements for glucose, glutamine and fatty acids for effector versus regulatory T cell development. Also tolerogenic dendritic cells mediate lowering of extracellular essential amino acids by their enhanced catabolism, promoting the induction of regulatory T cells. The purpose of this Research Topic is to provide an update on the current understanding of the multiple roles for metabolism in regulating the immune system.