Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric ...complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.
Future Needs in Mast Cell Biology Varricchi, Gilda; de Paulis, Amato; Marone, Gianni ...
International journal of molecular sciences,
09/2019, Letnik:
20, Številka:
18
Journal Article
Recenzirano
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The pathophysiological roles of mast cells are still not fully understood, over 140 years since their description by Paul Ehrlich in 1878. Initial studies have attempted to identify distinct ..."subpopulations" of mast cells based on a relatively small number of biochemical characteristics. More recently, "subtypes" of mast cells have been described based on the analysis of transcriptomes of anatomically distinct mouse mast cell populations. Although mast cells can potently alter homeostasis, in certain circumstances, these cells can also contribute to the restoration of homeostasis. Both solid and hematologic tumors are associated with the accumulation of peritumoral and/or intratumoral mast cells, suggesting that these cells can help to promote and/or limit tumorigenesis. We suggest that at least two major subsets of mast cells, MC1 (meaning anti-tumorigenic) and MC2 (meaning pro-tumorigenic), and/or different mast cell mediators derived from otherwise similar cells, could play distinct or even opposite roles in tumorigenesis. Mast cells are also strategically located in the human myocardium, in atherosclerotic plaques, in close proximity to nerves and in the aortic valve. Recent studies have revealed evidence that cardiac mast cells can participate both in physiological and pathological processes in the heart. It seems likely that different subsets of mast cells, like those of cardiac macrophages, can exert distinct, even opposite, effects in different pathophysiological processes in the heart. In this chapter, we have commented on possible future needs of the ongoing efforts to identify the diverse functions of mast cells in health and disease.
Eosinophils: The unsung heroes in cancer? Varricchi, Gilda; Galdiero, Maria Rosaria; Loffredo, Stefania ...
Oncoimmunology,
02/2018, Letnik:
7, Številka:
2
Journal Article
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Prolonged low-grade inflammation or smoldering inflammation is a hallmark of a cancer. Eosinophils are components of the immune microenvironment that modulates tumor initiation and progression. ...Although canonically associated with a detrimental role in allergic disorders, these cells can induce a protective immune response against helminthes, viral and bacterial pathogens. Eosinophils are a source of anti-tumorigenic (e.g., TNF-α, granzyme, cationic proteins, and IL-18) and protumorigenic molecules (e.g., pro-angiogenic factors) depending on the milieu. In several neoplasias (e.g., melanoma, gastric, colorectal, oral and prostate cancer) eosinophils play an anti-tumorigenic role, in others (e.g., Hodgkin's lymphoma, cervical carcinoma) have been linked to poor prognosis, whereas in yet others they are apparently innocent bystanders. These seemingly conflicting results suggest that the role of eosinophils and their mediators could be cancer-dependent. The microlocalization (e.g., peritumoral vs intratumoral) of eosinophils could be another important aspect in the initiation/progression of solid and hematological tumors. Increasing evidence in experimental models indicates that activation/recruitment of eosinophils could represent a new therapeutic strategy for certain tumors (e.g., melanoma). Many unanswered questions should be addressed before we understand whether eosinophils are an ally, adversary or neutral bystanders in different types of human cancers.
•Angiogenesis and lymphangiogenesis are activated during tumor growth and chronic inflammation.•Macrophages, mast cells, basophils, neutrophils, monocytes, and eosinophils produce angiogenic ...factors.•Neutrophils can also release anti-angiogenic factors.•Immune cells are also a target of angiogenic/lymphangiogenic factors.•Immune cells are possible targets in chronic inflammatory disorders and tumors.
Angiogenesis and lymphangiogenesis are distinct and complex processes requiring a finely tuned balance between stimulatory and inhibitory signals. During adulthood, angiogenesis and lymphangiogenesis are activated at sites of tumor growth, tissue injury and remodeling, and chronic inflammation. Vascular endothelial growth factors (VEGFs), angiopoietin (ANGPTs) and a multitude of additional signaling molecules play distinct roles in the modulation of angiogenesis/lymphangiogenesis. VEGFs and ANGPTs activate specific tyrosine kinase receptor (e.g., VEGFR1, VEGFR-2, VEGFR-3 and TIE2 respectively), expressed on blood endothelial cells (angiogenesis) and lymphatic endothelial cells (lymphangiogenesis). Although tumor cells produce VEGFs and other proangiogenic mediators, tissue resident (e.g., macrophages, mast cells) and circulating immune cells (e.g., basophils, neutrophils, monocytes, eosinophils) are an important source of angiogenic/lymphangiogenic mediators in inflammation and in tumor microenvironment and at site of chronic inflammation. Certain immune cells can also release anti-angiogenic factors. Mast cells, basophils, neutrophils and presumably other immune cells are not only a source of angiogenic/lymphangiogenic molecules, but also their target. Cells of the immune system need consideration as major players and possible targets for therapeutic manipulation of angiogenesis/lymphangiogenesis in chronic inflammatory disorders and tumors.
A hallmark of cancer is the ability of tumor cells to avoid immune destruction. Activated immune cells in tumor microenvironment (TME) secrete proinflammatory cytokines and chemokines which foster ...the proliferation of tumor cells. Specific antigens expressed by cancer cells are recognized by the main actors of immune response that are involved in their elimination (immunosurveillance). By the recruitment of immunosuppressive cells, decreasing the tumor immunogenicity, or through other immunosuppressive mechanisms, tumors can impair the host immune cells within the TME and escape their surveillance. Within the TME, cells of the innate (e.g., macrophages, mast cells, neutrophils) and the adaptive (e.g., lymphocytes) immune responses are interconnected with epithelial cancer cells, fibroblasts, and endothelial cells via cytokines, chemokines, and adipocytokines. The molecular pattern of cytokines and chemokines has a key role and could explain the involvement of the immune system in tumor initiation and progression. Thyroid cancer-related inflammation is an important target for diagnostic procedures and novel therapeutic strategies. Anticancer immunotherapy, especially immune checkpoint inhibitors, unleashes the immune system and activates cytotoxic lymphocytes to kill cancer cells. A better knowledge of the molecular and immunological characteristics of TME will allow novel and more effective immunotherapeutic strategies in advanced thyroid cancer.
Gastric cancer is diagnosed in nearly one million new patients each year and it remains the second leading cause of cancer-related deaths worldwide. Although gastric cancer represents a heterogeneous ...group of diseases, chronic inflammation has been shown to play a role in tumorigenesis. Cancer development is a multistep process characterized by genetic and epigenetic alterations during tumour initiation and progression. The stromal microenvironment is important in maintaining normal tissue homeostasis or promoting tumour development. A plethora of immune cells (i.e., lymphocytes, macrophages, mast cells, monocytes, myeloid-derived suppressor cells, Treg cells, dendritic cells, neutrophils, eosinophils, natural killer (NK) and natural killer T (NKT) cells) are components of gastric cancer microenvironment. Mast cell density is increased in gastric cancer and there is a correlation with angiogenesis, the number of metastatic lymph nodes and the survival of these patients. Mast cells exert a protumorigenic role in gastric cancer through the release of angiogenic (VEGF-A, CXCL8, MMP-9) and lymphangiogenic factors (VEGF-C and VEGF-F). Gastric mast cells express the programmed death ligands (PD-L1 and PD-L2) which are relevant as immune checkpoints in cancer. Several clinical undergoing trials targeting immune checkpoints could be an innovative therapeutic strategy in gastric cancer. Elucidation of the role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization.
Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs physiologically in wound healing, during inflammatory diseases, and in tumor growth. Lymphangiogenesis can be activated ...in inflammation and tumor metastasis. The family of vascular endothelial growth factors (VEGFs) and angiopoietins are essential for angiogenesis and lymphangiogenesis. The angiogenic process is tightly regulated by VEGFs, angiopoietins, and endogenous inhibitors. VEGFs and angiopoietins exert their effects by activating specific receptors present on blood and lymphatic endothelial cells. There is now compelling evidence that cells of innate and adaptive immunity (macrophages, mast cells, neutrophils, eosinophils, lymphocytes) are a major source of angiogenic and lymphangiogenic factors. Chronic inflammatory skin diseases such as psoriasis and atopic dermatitis are characterized by altered angiogenesis, lymphangiogenesis, or both. Also such acute inflammatory skin disorders as urticaria, ultraviolet B–induced damage, and angioedema are associated with changes in angiogenic factors. In systemic sclerosis there is a switch from proangiogenic to antiangiogenic factors that play a role in the defective vascular process of this disorder. As yet, there are no clinical trials showing that canonical VEGF/VEGF receptor-targeted strategies can modulate inflammatory skin diseases. Novel strategies targeting other angiogenic/lymphangiogenic pathways should also be investigated.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and inteleukin-3 (IL-3) have long been known as mediators of emergency myelopoiesis, but recent evidence has highlighted their critical role ...in modulating innate immune effector functions in mice and humans. This new wealth of knowledge has uncovered novel aspects of the pathogenesis of a range of disorders, including infectious, neoplastic, autoimmune, allergic and cardiovascular diseases. Consequently, GM-CSF and IL-3 are now being investigated as therapeutic targets for some of these disorders, and some phase I/II clinical trials are already showing promising results. There is also pre-clinical and clinical evidence that GM-CSF can be an effective immunostimulatory agent when being combined with anti-cytotoxic T lymphocyte-associated protein 4 (anti-CTLA-4) in patients with metastatic melanoma as well as in novel cancer immunotherapy approaches. Finally, GM-CSF and to a lesser extent IL-3 play a critical role in experimental models of trained immunity by acting not only on bone marrow precursors but also directly on mature myeloid cells. Altogether, characterizing GM-CSF and IL-3 as central mediators of innate immune activation is poised to open new therapeutic avenues for several immune-mediated disorders and define their potential in the context of immunotherapies.
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