Experientia supplementum (2012)最新文献

Myeloid-derived suppressor cells (MDSCs) are immature bone marrow-derived suppressive cells that are an important component of the pathological immune response associated with cancer. Expansion of MDSCs has been linked to poor disease outcome and therapeutic resistance in patients with various malignancies, making these cells potential targets for next-generation treatment strategies. MDSCs are classified into monocytic (M-MDSC) and polymorphonuclear/granulocytic (PMN-MDSC) subtypes that undertake distinct and numerous roles in the tumor microenvironment or systemically to drive disease progression. In this chapter, we will discuss how MDSC subsets contribute to the growth of primary tumors and induce metastatic spread by suppressing the antitumor immune response, supporting cancer stem cell (CSC)/epithelial-to-mesenchymal transition (EMT) phenotypes and promoting angiogenesis. We will also summarize the signaling networks involved in the crosstalk between cancer cells and MDSCs that could represent putative immunotherapy targets.

Microsporidia are obligate intracellular pathogens that were initially identified about 160 years ago. Current phylogenetic analysis suggests that they are grouped with Cryptomycota as a basal branch or sister group to the fungi. Microsporidia are found worldwide and can infect a wide range of animals from invertebrates to vertebrates, including humans. They are responsible for a variety of diseases once thought to be restricted to immunocompromised patients but also occur in immunocompetent individuals. The small oval spore containing a coiled polar filament, which is part of the extrusion and invasion apparatus that transfers the infective sporoplasm to a new host, is a defining characteristic of all microsporidia. When the spore becomes activated, the polar filament uncoils and undergoes a rapid transition into a hollow tube that will transport the sporoplasm into a new cell. The polar tube has the ability to increase its diameter from approximately 100 nm to over 600 nm to accommodate the passage of an intact sporoplasm and penetrate the plasmalemma of the new host cell. During this process, various polar tube proteins appear to be involved in polar tube attachment to host cell and can interact with host proteins. These various interactions act to promote host cell infection.

Natural Killer (NK) cells are effector lymphocytes with the ability to generate an antitumor response. NK cells encompass a diverse group of subsets with different properties and have the capacity to kill cancer cells by different means. However, tumor cells have developed several mechanisms to evade NK cell-mediated killing. In this chapter, we summarize some aspects of NK cell biology with the aim to understand the competence of these cells and explore some of the challenges that NK cells have to face in different malignancies. Moreover, we will review the current knowledge about the role of NK cells in tumor progression and describe their phenotype and effector functions in tumor tissues and peripheral blood from cancer patients. Finally, we will recapitulate several findings from different studies focused on determining the prognostic value of NK cells in distinct cancers.

Microsporidia are poorly understood, ubiquitous eukaryotic parasites that are completely dependent on their hosts for replication. With the discovery of microsporidia species naturally infecting the genetically tractable transparent nematode C. elegans, this host has been used to explore multiple areas of microsporidia biology. Here we review results about microsporidia infections in C. elegans, which began with the discovery of the intestinal-infecting species Nematocida parisii. Recent findings include new species identification in the Nematocida genus, with more intestinal-infecting species, and also a species with broader tissue tropism, the epidermal and muscle-infecting species Nematocida displodere. This species has a longer polar tube infection apparatus, which may enable its wider tissue range. After invasion, multiple Nematocida species appear to fuse host cells, which likely promotes their dissemination within host organs. Localized proteomics identified Nematocida proteins that have direct contact with the C. elegans intestinal cytosol and nucleus, and many of these host-exposed proteins belong to expanded, species-specific gene families. On the host side, forward genetic screens have identified regulators of the Intracellular Pathogen Response (IPR), which is a transcriptional response induced by both microsporidia and the Orsay virus, which is also a natural, obligate intracellular pathogen of the C. elegans intestine. The IPR constitutes a novel immune/stress response that promotes resistance against microsporidia, virus, and heat shock. Overall, the Nematocida/C. elegans system has provided insights about strategies for microsporidia pathogenesis, as well as innate defense pathways against these parasites.

Tumor-infiltrating lymphocytes (TIL) are an important component of the tumor environment. Their role in tumor growth and progression has been debated for decades. Today, emphasis has shifted to beneficial effects of TIL for the host and to therapies optimizing the benefits by reducing immune suppression in the tumor microenvironment. Evidence indicates that when TILs are present in the tumor as dense aggregates of activated immune cells, tumor prognosis and responses to therapy are favorable. Gene signatures and protein profiling of TIL at the population and single-cell levels provide clues not only about their phenotype and numbers but also about TIL potential functions in the tumor. Correlations of the TIL data with clinicopathological tumor characteristics, clinical outcome, and patients' survival indicate that TILs exert influence on the disease progression, especially in colorectal carcinomas and breast cancer. At the same time, the recognition that TIL signatures vary with time and cancer progression has initiated investigations of TIL as potential prognostic biomarkers. Multiple mechanisms are utilized by tumors to subvert the host immune system. The balance between pro- and antitumor responses of TIL largely depends on the tumor microenvironment, which is unique in each cancer patient. This balance is orchestrated by the tumor and thus is shifted toward the promotion of tumor growth. Changes occurring in TIL during tumor progression appear to serve as a measure of tumor aggressiveness and potentially provide a key to selecting therapeutic strategies and inform about prognosis.

Tumor microenvironment (TME) is a complex and constantly evolving entity that consists not only of cancer cells, but also of resident host cells and immune-infiltrating cells, among which macrophages are significant components, due to their diversity of functions through which they can influence the immune response against tumor cells. Macrophages present in tumor environment are termed as tumor-associated macrophages (TAMs). They are strongly plastic cells, and depending on the TME stimuli (i.e., cytokines, chemokines), TAMs polarize to antitumoral (M1-like TAMs) or protumoral (M2-like TAMs) phenotype. Both types of TAMs differ in the surface receptors' expression, activation of intracellular signaling pathways, and ability of production and various metabolites release. At the early stage of tumor formation, TAMs are M1-like phenotype, and they are able to eliminate tumor cells, i.e., by reactive oxygen species formation or by presentation of cancer antigens to other effector immune cells. However, during tumor progression, TAMs M2-like phenotype is dominating. They mainly contribute to angiogenesis, stromal remodeling, enhancement of tumor cells migration and invasion, and immunosuppression. This wide variety of TAMs' functions makes them an excellent subject for use in developing antitumor therapies which mainly is based on three strategies: TAMs' elimination, reprograming, or recruitment inhibition.

The immune checkpoint cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 or CD152) is a negative regulator of T-cell-mediated immune responses which plays a critical role in suppressing autoimmunity and maintaining immune homeostasis. Because of its inhibitory activity on T cells, CTLA-4 has been investigated as a drug target to induce immunostimulation, blocking the interaction with its ligands. The antitumor effects mediated by CTLA-4 blockade have been attributed to a sustained active immune response against cancer cells, due to the release of a brake on T cell activation. Ipilimumab (Yervoy, Bristol-Myers Squibb) is a fully human anti-CTLA-4 IgG1κ monoclonal antibody (mAb) that represents the first immune checkpoint inhibitor approved as monotherapy by FDA and EMA in 2011 for the treatment of unresectable/metastatic melanoma. In 2015, FDA also granted approval to ipilimumab monotherapy as adjuvant treatment of stage III melanoma to reduce the risk of tumour recurrence. The subsequent approved indications of ipilimumab for metastatic melanoma, regardless of BRAF mutational status, and other advanced/metastatic solid tumours always involve its use in association with the anti-programmed cell death protein 1 (PD-1) mAb nivolumab. Currently, ipilimumab is evaluated in ongoing clinical trials for refractory/advanced solid tumours mainly in combination with additional immunostimulating agents.

Analytical methods developed for studying immunoglobulin glycosylation rely heavily on software tailored for this purpose. Many of these tools are now used in high-throughput settings, especially for the glycomic characterization of IgG. A collection of these tools, and the databases they rely on, are presented in this chapter. Specific applications are detailed in examples of immunoglobulin glycomics and glycoproteomics data processing workflows. The results obtained in the glycoproteomics workflow are emphasized with the use of dedicated visualizing tools. These tools enable the user to highlight glycan properties and their differential expression.

Mass spectrometry and its hyphenated techniques enabled by the improvements in liquid chromatography, capillary electrophoresis, novel ionization, and fragmentation modes are truly a cornerstone of robust and reliable protein glycosylation analysis. Boost in immunoglobulin G (IgG) glycan and glycopeptide profiling demands for both applied biomedical and research applications has brought many new advances in the field in terms of technical innovations, sample preparation, improved throughput, and confidence in glycan structural characterization. This chapter summarizes mass spectrometry basics, focusing on IgG and monoclonal antibody N-glycosylation analysis on several complexity levels. Different approaches, including antibody enrichment, glycan release, labeling, and glycopeptide preparation and purification, are covered and illustrated with recent breakthroughs and examples from the literature omitting excessive theoretical frameworks. Finally, selected highly popular methodologies in IgG glycoanalytics such as liquid chromatography-mass spectrometry and matrix-assisted laser desorption ionization are discussed more thoroughly yet in simple terms making this text a practical starting point either for the beginner in the field or an experienced clinician trying to make sense out of the IgG glycomic or glycoproteomic dataset.

Alternative glycosylation of immunoglobulin G (IgG) affects its effector functions during the immune response. IgG glycosylation is altered in many diseases, but also during a healthy life of an individual. Currently, there is limited knowledge of factors that alter IgG glycosylation in the healthy state and factors involved in specific IgG glycosylation patterns associated with pathophysiology. Genetic background plays an important role, but epigenetic mechanisms also contribute to the alteration of IgG glycosylation patterns in healthy life and in disease. It is known that the expression of many glycosyltransferases is regulated by DNA methylation and by microRNA (miRNA) molecules, but the involvement of other epigenetic mechanisms, such as histone modifications, in the regulation of glycosylation-related genes (glycogenes) is still poorly understood. Recent studies have identified several differentially methylated loci associated with IgG glycosylation, but the mechanisms involved in the formation of specific IgG glycosylation patterns remain poorly understood.