scholarly journals Immunosenescence: a key player in cancer development

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Jingyao Lian ◽  
Ying Yue ◽  
Weina Yu ◽  
Yi Zhang
Keyword(s):  
T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Killer Cell ◽  
Antibody Therapy ◽  
The Elderly ◽  
Mtor Inhibition ◽  
Interleukin 7 ◽  
The Many

Abstract Immunosenescence is a process of immune dysfunction that occurs with age and includes remodeling of lymphoid organs, leading to changes in the immune function of the elderly, which is closely related to the development of infections, autoimmune diseases, and malignant tumors. T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species. Senescent T cells exhibit abnormal phenotypes, including downregulation of CD27, CD28, and upregulation of CD57, killer cell lectin-like receptor subfamily G, Tim-3, Tight, and cytotoxic T-lymphocyte-associated protein 4, which are tightly related to malignant tumors. The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells. Accordingly, these senescent immune cells could also affect tumor progression. In addition, the effect of immunosenescence on the response to immune checkpoint blocking antibody therapy so far is ambiguous due to the low participation of elderly cancer patients in clinical trials. Furthermore, many other senescence-related interventions could be possible with genetic and pharmacological methods, including mTOR inhibition, interleukin-7 recombination, and NAD+ activation. Overall, this review aims to highlight the characteristics of immunosenescence and its impact on malignant tumors and immunotherapy, especially the future directions of tumor treatment through senescence-focused strategies.

scholarly journals Role of Immunogenetics in the Outcome of HCMV Infection: Implications for Ageing

2019 ◽  
Vol 20 (3) ◽  
pp. 685 ◽  
Author(s):  
Anna Aiello ◽  
Giulia Accardi ◽  
Giuseppina Candore ◽  
Calogero Caruso ◽  
Claudia Colomba ◽  
...  
Keyword(s):  
Hcmv Infection ◽  
Killer Cell ◽  
Human Leukocyte ◽  
The Elderly ◽  
Point Of View ◽  
Italian Population ◽  
Symptomatic Infection ◽  
Humoral And Cellular Immunity ◽  
Gm Allotypes

The outcome of host-virus interactions is determined by a number of factors, some related to the virus, others to the host, such as environmental factors and genetic factors. Therefore, different individuals vary in their relative susceptibility to infections. Human cytomegalovirus (HCMV) is an important pathogen from a clinical point of view, as it causes significant morbidity and mortality in immunosuppressed or immunosenescent individuals, such as the transplanted patients and the elderly, respectively. It is, therefore, important to understand the mechanisms of virus infection control. In this review, we discuss recent advances in the immunobiology of HCMV-host interactions, with particular emphasis on the immunogenetic aspects (human leukocyte antigens, HLA; killer cell immunoglobulin-like receptors, KIRs; immunoglobulin genetic markers, GM allotypes) to elucidate the mechanisms underlying the complex host-virus interaction that determine various outcomes of HCMV infection. The results, which show the role of humoral and cellular immunity in the control of infection by HCMV, would be valuable in directing efforts to reduce HCMV spurred health complications in the transplanted patients and in the elderly, including immunosenescence. In addition, concerning GM allotypes, it is intriguing that, in a Southern Italian population, alleles associated with the risk of developing HCMV symptomatic infection are negatively associated with longevity.

KIR Positive Subsets of Human CD56+CD3+ NKT Cells Are Different in Frequency from Equivalant KIR Positive CD56+CD3- NK Cell Subsets.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3878-3878
Author(s):  
Ilka Bondzio ◽  
Andreas Arendt ◽  
Jurgen Schmitz ◽  
Volker Huppert
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Nk Cell ◽  
Cytotoxic T Cells ◽  
Killer Cell ◽  
Nkt Cells ◽  
Nkt Cell ◽  
Cell Clones ◽  
Number Of Publications

Abstract Killer cell immunoglobulin-like receptors (KIRs) are known to modulate the cytotoxic ability of human Natural Killer (NK) cells, as well as a subset of T cells. To date, only a very small number of publications have discussed the role of KIRs on T cells, e.g. CMV-specific CD4+CD28-KIR+ cytotoxic T cells (van Bergen, J., J Immunol. 2004), so we investigated whether CD56+CD3+ NKT cells might also have KIR-positive subsets. Whole human blood as well as magnetically sorted human CD56+CD3+ NKT cells were analyzed for their expression of various KIR molecules using a novel panel of fluorochrome-conjugated, anti-KIR monoclonal antibodies (CD158a/h (KIR2DL1/DS1), CD158b (KIR2DL2), CD158e (KIR3DL1), CD158i (KIR2DS4), KIR2D; Miltenyi Biotec). KIR-positive CD56+CD3+ NKT cells were identified in every donor tested. Donors possessing NK cells of a specific KIR phenotype also possessed CD56+CD3+ NKT cells with the same KIR phenotype. KIRs were also expressed in a clonal fashion on CD56+CD3+ NKT cells, similarly to NK cells. The investigated KIRs were also shown to be expressed on unseparated NK and CD56+CD3+ NKT cells from whole blood. In addition, the ratio between KIR expression on NK and CD56+CD3+ NKT cells was calculated for each donor analyzed. The results show that there is no correlation between the frequencies of KIR expression on NK cells with that of CD56+CD3+ NKT cells. For example, the expression of CD158a/h in one donor was found to be the highest of all CD56+CD3+ NKT cells analyzed, but the lowest of all NK cells by comparison to the other donors tested. For all KIR phenotypes analyzed, the frequency of KIR+ NK cells was higher than the frequency of KIR+ CD56+CD3+ NKT cells in all samples (range: 1.1 to 25.3-fold higher). Interestingly, the frequency of KIR+ NK cells versus KIR+ CD56+CD3+ NKT cells differs significantly between donors: in one donor the frequency of KIR expression is between 7.3 to 25.3-fold higher in NK cells for multiple KIR phenotypes, while this range is more narrow in other donors (2.0–5.4-fold higher). The frequencies of CD56+CD3+ NKT cell subsets staining positive for particular KIRs differ significantly between donors, e.g. for CD158b, the number of positive CD56+CD3+ NKT cells fall within a range of 4.8% to 43.3%. For CD56+CD3+ NKT cells sorted with MACS® Technology, a similarly wide-ranging distribution of CD158b (KIR2DL2) expression was found (0.85%–5.82%), though at a lower level. Further research will be required to explore these differences as they may point to different mechanisms of KIR regulation. The identification of KIR-positive CD56+CD3+ NKT cells may also provide an opportunity for their use for functional KIR studies instead of NK cell clones, as the cloning of CD56+CD3+ NKT cells may prove easier (i.e. using standard T cell cloning methods) than that of NK cells.

scholarly journals DUSP12 regulates the tumorigenesis and prognosis of hepatocellular carcinoma

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11929
Author(s):  
Gaoda Ju ◽  
Tianhao Zhou ◽  
Rui Zhang ◽  
Xiaozao Pan ◽  
Bing Xue ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Immune Cells ◽  
Malignant Tumors ◽  
Critical Role ◽  
Normal Liver ◽  
Functional Enrichment ◽  
Loss Of Function ◽  
Liver Tissues

Background Dual specificity protein phosphatase (DUSP)12 is an atypical member of the protein tyrosine phosphatase family, which are overexpressed in multiple types of malignant tumors. This protein family protect cells from apoptosis and promotes the proliferation and motility of cells. However, the pathological role of DUSP12 in hepatocellular carcinoma (HCC) is incompletely understood. Methods We analyzed mRNA expression of DUSP12 between HCC and normal liver tissues using multiple online databases, and explored the status of DUSP12 mutants using the cBioPortal database. The correlation between DUSP12 expression and tumor-infiltrating immune cells was demonstrated using the Tumor Immune Estimation Resource database and the Tumor and Immune System Interaction Database. Loss of function assay was utilized to evaluate the role of DUSP12 in HCC progression. Results DUSP12 had higher expression along with mRNA amplification in HCC tissues compared with those in normal liver tissues, which suggested that higher DUSP12 expression predicted shorter overall survival. Analyses of functional enrichment of differentially expressed genes suggested that DUSP12 regulated HCC tumorigenesis, and that knockdown of DUSP12 expression by short hairpin (sh)RNA decreased the proliferation and migration of HCC cells. Besides, DUSP12 expression was positively associated with the infiltration of cluster of differentiation (CD)4+ T cells (especially CD4+ regulatory T cells), macrophages, neutrophils and dendritic cells. DUSP12 expression was positively associated with immune-checkpoint moieties, and was downregulated in a C3 immune-subgroup of HCC (which had the longest survival). Conclusion These data suggest that DUSP12 may have a critical role in the tumorigenesis, infiltration of immune cells, and prognosis of HCC.

scholarly journals Immune checkpoint blockade in the treatment of malignant tumor: current statue and future strategies

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wenwen Yang ◽  
Caining Lei ◽  
Shaoming Song ◽  
Wutang Jing ◽  
Chuanwei Jin ◽  
...  
Keyword(s):  
T Cells ◽  
Malignant Tumor ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Immune Surveillance ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Response ◽  
Inhibitory Molecule

AbstractAfter being stagnant for decades, there has finally been a paradigm shift in the treatment of cancer with the emergence and application of immune checkpoint inhibitors (ICIs). The most extensively utilized ICIs are targeting the pathways involving programmed death-1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4). PD-1, as an crucial immune inhibitory molecule, by and large reasons the immune checkpoint response of T cells, making tumor cells get away from immune surveillance. Programmed cell death ligand-1 (PD-L1) is exceptionally expressed in most cancers cells and approves non-stop activation of the PD-1 pathway in the tumor microenvironment. PD-1/PD-L1 inhibitors can block the combination of PD-1 and PD-L1, inhibit hostile to regulatory signals, and restore the activity of T cells, thereby bettering immune response. The current researchers assume that the efficacy of these drugs is related to PD-L1 expression in tumor tissue, tumor mutation burden (TMB), and other emerging biomarkers. Although malignant tumors can benefit from the immunotherapy of PD-1/PD-L1 inhibitors, formulating a customized medication model and discovering biomarkers that can predict efficacy are the new trend in the new era of malignant tumor immunotherapy. This review summarizes the mechanism of action of PD-1/PD-L1 inhibitors, their clinical outcomes on various malignant tumors, their efficacy biomarkers, as well as predictive markers of irAEs.

Downregulation of miR-633 activated AKT/mTOR pathway by targeting AKT1 in lupus CD4+ T cells

Lupus ◽  
2019 ◽  
Vol 28 (4) ◽  
pp. 510-519 ◽  
Author(s):  
S Chen ◽  
Y Wang ◽  
H Qin ◽  
J Lin ◽  
L Xie ◽  
...  
Keyword(s):  
T Cells ◽  
Western Blot ◽  
Lupus Erythematosus ◽  
Quantitative Polymerase Chain Reaction ◽  
Mtor Pathway ◽  
Jurkat Cells ◽  
Luciferase Assay ◽  
Mtor Inhibition ◽  
Direct Target

Background Accumulating evidence suggests that the AKT/mTOR pathway plays an important role in the pathogenesis of systemic lupus erythematosus (SLE) through activating T cells, and there are few studies looking into the role of microRNA (miRNAs) in the mechanism. We first found that miR-633 expression in CD4+T cells of SLE patients was significantly reduced. Objective To investigate the role of miR-633 in the AKT/mTOR pathway in lupus CD4+T cells. Methods Samples of 17 SLE cases and 16 healthy controls were collected to detect the expression of miR-633, AKT1, mTOR mRNA and proteins by quantitative polymerase chain reaction (qPCR) and Western-blot, respectively. To determine whether AKT1 is a direct target of miR-633, a luciferase assay was performed. In vitro, AKT1 siRNA, miR-633 mimics/inhibitors or negative controls were transfected to Jurkat cells, human primary CD4+T cells and lupus CD4+T cells. RNA and proteins were extracted after 48 h, and levels of AKT/mTOR pathway markers and downstream multiple cytokines were detected by qPCR or Western-blot. Results In SLE patients, the miR-633 levels in CD4+T cells were significantly decreased and negatively correlated with SLEDAI. AKT1, mTOR mRNA and proteins were all up-regulated. The degree of downregulation of miR-633 was correlated negatively with AKT1 mRNA. The luciferase assay proved that AKT1 is a direct target of miR-633. In Jurkat and lupus CD4+T cells, overexpression of miR-633 could result in lower levels of AKT1 and mTOR. Inhibition of miR-633 expression in primary CD4+T cells caused reverse effects, and protein levels of p-AKT, p-mTOR, and p-S6RP increased. Moreover, among various cytokines, the expression of IL-4, IL-17, and IFN-γ mRNA was raised. Conclusion Our study suggests that miR-633 deletion can activate the AKT/mTOR pathway by targeting AKT1 to participate in the pathogenesis of SLE.

scholarly journals The Role of the Status of Selected Micronutrients in Shaping the Immune Function

2019 ◽  
Vol 19 (8) ◽  
pp. 1100-1115 ◽  
Author(s):  
Ibrahim Elmadfa ◽  
Alexa L. Meyer
Keyword(s):  
T Cells ◽  
Cellular Immunity ◽  
Viral Infections ◽  
Cell Signalling ◽  
The Elderly ◽  
Immune Defence ◽  
Th1 Cell ◽  
Special Effects ◽  
T Cell Subpopulations

Objective: This narrative review gives an overview on the essential role of adequate nutrition to an optimally functioning immune defence. Micronutrients act as regulators of the immune response, with the focus of this review on the immunomodulatory effects of the trace elements iron, zinc and selenium, and the vitamins A, D, E, C, B6 and B12 and folic acid. Results: Iron deficiency especially impairs the Th1 cell-borne cellular immunity. T lymphocytes are also most affected by a deficiency of zinc, needed for their maturation and the balance between the different T cell subpopulations and acting as a redox signal in the regulation of many enzymes. Selenium is also involved in redox reactions as the glutathione peroxidases and other redox enzymes are selenoproteins. Selenium status has shown special effects on cellular immunity and resistance to viral infections. : Vitamin A in the form of retinoic acid induces a humoral Th2 cell response via antigen-presenting cells and is involved in maintaining intestinal immune defence and tolerance through its nuclear receptor RAR and via kinase signalling cascades. Immune tolerance is particularly promoted by vitamin D acting through dendritic cells to stimulate the differentiation of regulatory T cells. Vitamin E has antiinflammatory effects and stimulates naïve T cells especially in the elderly. Besides its antioxidative properties, vitamin C has effects on cell signalling and epigenetic regulation. The B vitamins are required for cytotoxic cellular immunity and modulateT cell responses. : A diverse diet and regular exposure to sunlight are the best sources for a balanced nutrient supply to maintain an optimal immune defence.

scholarly journals Reduced Ebola vaccine responses in CMV+ young adults is associated with expansion of CD57+KLRG1+ T cells

2020 ◽  
Vol 217 (7) ◽  
Author(s):  
Georgina Bowyer ◽  
Hannah Sharpe ◽  
Navin Venkatraman ◽  
Pierre Birahim Ndiaye ◽  
Djibril Wade ◽  
...  
Keyword(s):  
T Cells ◽  
Young Adults ◽  
Killer Cell ◽  
Adenovirus Type ◽  
The Elderly ◽  
Younger Adults ◽  
Vaccine Responses ◽  
Cell Responses ◽  
Type 3 ◽  
The Impact

CMV is associated with immunosenescence and reduced vaccine responses in the elderly (>70 yr). However, the impact of CMV in young adults is less clear. In this study, healthy UK and Senegalese adults aged 18–50 yr (average, 29 yr) were vaccinated with the Ebola vaccine candidate chimpanzee adenovirus type 3–vectored Ebola Zaire vaccine (ChAd3-EBO-Z) and boosted with modified vaccinia Ankara Ebola Zaire–vectored (MVA–EBO-Z) vaccine. CMV carriage was associated with an expansion of phenotypically senescent CD4+ and CD8+ T cells expressing CD57 and killer cell lectin-like receptor G1 (KLRG1), which was negatively associated with vaccine responses in both cohorts. Ebola-specific T cell responses induced by vaccination also contained significantly increased frequencies of terminally differentiated CD57+KLRG1+ cells in CMV seropositive (CMV+) individuals. This study suggests that CMV can also affect vaccine responses in younger adults and may have a particularly marked impact in many developing countries where CMV seroprevalence is almost universal.

scholarly journals Development of regulatory T cells requires IL-7Rα stimulation by IL-7 or TSLP

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3283-3292 ◽  
Author(s):  
Renata Mazzucchelli ◽  
Julie A. Hixon ◽  
Rosanne Spolski ◽  
Xin Chen ◽  
Wen Qing Li ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Cytotoxic T Lymphocyte ◽  
Treg Cells ◽  
Lymphoid Tissues ◽  
Normal Numbers ◽  
Thymic Development ◽  
Interleukin 7 ◽  
Forkhead Box ◽  
Necrosis Factor

Abstract Interleukin-7 (IL-7), a cytokine produced by stromal cells, is required for thymic development and peripheral homeostasis of most major subsets of T cells. We examined whether regulatory T (Treg) cells also required the IL-7 pathway by analyzing IL-7Rα−/− mice. We observed a striking reduction in cells with the Treg surface phenotype (CD4, CD25, GITR (glucocorticoid-induced tumor necrosis factor [TNF]-like receptor), CD45RB, CD62L, CD103) or intracellular markers (cytotoxic T-lymphocyte–associated antigen-4, CTLA-4, and forkhead box transcription factor 3, Foxp3). Foxp3 transcripts were virtually absent in IL-7Rα−/− lymphoid tissues, and no Treg cell suppressive activity could be detected. There are 2 known ligands for IL-7Rα: IL-7 itself and thymic stromal lymphopoietin (TSLP). Surprisingly, mice deficient in IL-7 or the other chain of the TSLP receptor (TSLPR) developed relatively normal numbers of Treg cells. Combined deletion of IL-7 and TSLP receptor greatly reduced Treg cell development in the thymus but was not required for survival of mature peripheral Treg cells. We conclude that Treg cells, like other T cells, require signals from the IL-7 receptor, but unlike other T cells, do not require IL-7 itself because of at least partially overlapping actions of IL-7 and TSLP for development of Treg cells.

scholarly journals Physiotherapist's work at the Oncological Ward - stress and professional burnout

2018 ◽  
Vol 21 (3) ◽  
pp. 35-42
Author(s):  
Magdalena Pieniążek ◽  
Grzegorz Mańko ◽  
Joanna Skupień
Keyword(s):  
Medical Staff ◽  
Malignant Tumors ◽  
The Elderly ◽  
Survey Method ◽  
Subjective Perception ◽  
Professional Burnout ◽  
Negative Effects ◽  
Mental Strain ◽  
Not At Risk

Introduction: There are now more and more cases of malignant tumors. This is a problem that can affect anyone − from a baby to the elderly. The direct burden is on the patient and his/her immediate surroundings, however, all medical staff are involved in therapy, and are committed to doing everything to improve the condition of a patient. In the treatment process, the role of physiotherapy is essential and its effectiveness has been demonstrated by a number of scientifi c studies. Due to the large number of hours spent with the patient, therapists may be exposed to the negative effects of working in such a demanding ward. Aim: The aim of this study was to examine the subjective perception of physiotherapists work at Oncological Wards on stress and burnout. Material and Methods: The diagnostic survey method was used via a questionnaire. Data from 60 physiotherapists were analysed statistically. Results: Most defi ne work as stressful and mentally demanding. Nearly half of respondents believe that they are not at risk of professional burnout. Work in this ward is chosen for various reasons, which is refl ected in the feeling of mental strain. Conclusions: Working in the Oncology Ward creates the risk of stress and burnout in medical staff. oncological physiotherapy, professional burnout, stress, oncological ward

scholarly journals TIM-3 as a Prognostic Marker and a Potential Immunotherapy Target in Human Malignant Tumors: A Meta-Analysis and Bioinformatics Validation

2021 ◽  
Vol 11 ◽  
Author(s):  
Kui Zang ◽  
Liangliang Hui ◽  
Min Wang ◽  
Ying Huang ◽  
Xingxing Zhu ◽  
...  
Keyword(s):  
Functional Analysis ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
T Cell Activation ◽  
Malignant Tumors ◽  
Killer Cell ◽  
Cell Lung Carcinoma ◽  
Cox Regression Analysis

BackgroundAs a novel immune checkpoint molecular, T-cell immunoglobulin mucin 3 (TIM-3) is emerging as a therapeutic target for cancer immunotherapy. However, the predictive role of TIM-3 in cancer remains largely undetermined. This study was designed to investigate the role of TIM-3 in cancer.MethodsPublications were searched using multiple databases. The hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. To further confirm the prognostic effect of TIM-3, The Cancer Genome Atlas (TCGA) data were applied. Functional analysis of TIM-3 was also investigated.Results28 studies with 7284 patients with malignant tumors were identified. Based on multivariate Cox regression analysis, TIM-3 was an independent prognostic indicator for poor overall survival (OS) (HR= 1.54, 95% CI = 1.19-1.98, P = 0.001). However, TIM-3 was not correlated with cancer-specific survival and disease-free survival (DFS). Particularly, TIM-3 showed a worse prognosis in non-small cell lung carcinoma and gastric cancer; but it showed a favorable prognosis in breast cancer. Functional analysis showed that TIM-3 was closely correlated with immune responses such as T-cell activation and natural killer cell-mediated cytotoxicity. Moreover, TIM-3 expression was found to be related to worse OS in 9491 TCGA patients (HR = 1.2, P < 0.001), but was not associated with DFS.ConclusionsTIM-3 was an independent prognostic factor. Meanwhile, TIM-3 played a crucial role in tumor immune responses. This supports TIM-3 as a promising target for cancer immunotherapy.

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