669 research outputs found
Viral Hepatitides, Inflammation and Tumour Microenvironment
No full textIn this chapter, we discuss the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in the establishment of hepatocellular carcinoma (HCC), highlighting the key role of the multiple, non-mutually exclusive, pathways involved in the modulation of immune responses and in the orchestration of a chronic low-level inflammation state favouring HCC development. In particular, we discuss (i) HCC as a classical paradigm of inflammation-linked cancer; (ii) the role of the most relevant inflammatory cytokines involved (i.e. IL-6, TNF-α, IL-18, IL-1β, TGF-β IL-10); (iii) the role of T cell exhaustion by immune checkpoints; (iv) the role of the Wnt3a/β-catenin signalling pathway and (v) the role of different subsets of suppressor cells
Stromal circuits involving tumor-associated macrophages and cancer-associated fibroblasts
No full textThe tumor associated macrophages (TAM) represent one of most abundant subpopulations across several solid cancers and their number/frequency is associated with a poor clinical outcome. It has been clearly demonstrated that stromal cells, such as the cancer associated fibroblasts (CAFs), may orchestrate TAM recruitment, survival and reprogramming. Today, single cell-RNA sequencing (sc-RNA seq) technologies allowed a more granular knowledge about TAMs and CAFs phenotypical and functional programs. In this mini-review we discuss the recent discoveries in the sc-RNA seq field focusing on TAM and CAF identity and their crosstalk in the tumor microenvironment (TME) of solid cancers
CD39 Regulation and Functions in T Cells
No full textCD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer
CD39 Regulation and Functions in T Cells
No full textCD39 is an enzyme which is responsible, together with CD73, for a cascade converting adenosine triphosphate into adenosine diphosphate and cyclic adenosine monophosphate, ultimately leading to the release of an immunosuppressive form of adenosine in the tumor microenvironment. Here, we first review the environmental and genetic factors shaping CD39 expression. Second, we report CD39 functions in the T cell compartment, highlighting its role in regulatory T cells, conventional CD4+ T cells and CD8+ T cells. Finally, we compile a list of studies, from preclinical models to clinical trials, which have made essential contributions to the discovery of novel combinatorial approaches in the treatment of cancer
Circulating Neutrophils of Nonalcoholic Steatohepatitis Patients Show an Activated Phenotype and Suppress T Lymphocytes Activity
No full textNeutrophils or PolyMorphonuclear Neutrophils (PMNs) are key effector cells of the innate immune system and thanks to their remarkable plasticity, establish a cross talk with T cells modulating their survival and effector functions. During Nonalcoholic Steatohepatitis (NASH), the advanced form of hepatic steatosis or NAFL, PMNs infiltrate liver tissue, becoming a histological feature of NASH. Our aim was to evaluate the frequency of PMNs in NAFL and NASH patients in order to understand how they modulate the activity of circulating CD4+ and CD8+ T cells. In our cohort of patients, NASH patients displayed a higher frequency of circulating PMNs that was strongly correlated to liver enzymes, grade of steatosis, inflammation and fibrosis, the hepatocellular ballooning, and NAFLD Activity Score (NAS). Furthermore, even if ex vivo, in both groups of patients, PMNs shared the same phenotype of resting cells, after 24 hours of coculture with autologous CD4+ and CD8+ T cells, PMNs of NASH patients acquired a more active phenotype, becoming able to strongly inhibit proliferation and activation of CD4+ and CD8+ T cells. The higher ability of PMNs of NASH patients in suppressing CD4+ and CD8+ T cells, over time, might contribute in reducing the immunological defense of liver tissue against damages thus taking part in the progression of the NAFL disease toward NASH
'Hardcore' OX40(+) immunosuppressive regulatory T cells in hepatic cirrhosis and cancer
No full textHuman regulatory T cells (Tregs) comprise an array of distinct subsets displaying diverse functions in response to microenvironmental signals. Here, we review our recent findings demonstrating the preferential accumulation of uncommitted, Th1-like and OX40-Tregs in non-cirrhotic tissues in contrast to the presence of committed, Th1-suppressing and OX40(+) Tregs in cirrhotic and tumor contexts in human liver affected by chronic hepatitis C
Phenotypic and Functional Analysis of the Suppressive Function of Human Regulatory T Cells
No full textRegulatory T cells (Tregs) are defined as immunosuppressive cells playing crucial roles in the establishment and maintenance of immune homeostasis. During the course of immune responses, Tregs control the balance between host defense from pathogens and the prevention of excessive immunity. Here, we describe the phenotypic analysis of Tregs, evaluated in peripheral blood mononuclear cells of healthy adults, by multiparameter flow cytometry, which allows examining the expression of peculiar markers of Treg subpopulations with different features, and provides efficient discrimination of multiple characteristics at the single-cell level. The same technique may be applied to characterize mononuclear cells extracted from different specimens, including whole blood, biological fluids or solid tissues. The immunoregulatory identity of a certain Treg subpopulation may be functionally verified by performing an in vitro suppression assay described here, testing the capability of Tregs to suppress the activation of responder cells
ISG15 protects human Tregs from interferon alpha-induced contraction in a cell-intrinsic fashion
No full textObjectives: Type I interferons (IFNs) inhibit regulatory T-cell (Treg) expansion and activation, making them beneficial in antiviral responses, but detrimental in autoimmune diseases. Herein, we investigate the role of ISG15 in human Tregs in the context of refractoriness to type I IFN stimulation. Methods: ISG15 expression and Treg dynamics were analysed in vitro and ex vivo from patients with chronic hepatitis C, with lupus and ISG15 deficiency. Results: ISG15 is expressed at high levels in human Tregs, renders them refractory to the IFN-STAT1 signal, and protects them from IFN-driven contraction. In vitro, Tregs from healthy controls upregulate ISG15 upon activation to higher levels than conventional CD4 T cells, and ISG15-silenced Tregs are more susceptible to IFNα-induced contraction. In human ISG15 deficiency, patient Tregs display an elevated IFN signature relative to Tregs from healthy control. In vivo, in patients with chronic hepatitis C, 2 days after starting pegIFN/ribavirin therapy, a stronger ISG15 inducibility correlates with a milder Treg depletion. Ex vivo, in systemic lupus erythematosus patients, higher levels of ISG15 are associated to reduced STAT1 phosphorylation in response to IFNα, and also to increased frequencies of Tregs, characterising active disease. Conclusion: Our results reveal a Treg-intrinsic role of ISG15 in dictating their refractoriness to the IFN signal, thus preserving the Treg population under inflammatory conditions
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