scholarly journals Chemokines are Underestimated in Preventing the Metastasizing and the Immune Elimination of Ovarian Cancer

2019 ◽  
Author(s):  
Ruurd Torensma ◽  
Petra Zusterzeel
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Adaptive Immune Response ◽  
Inhibitory Response ◽  
T Cell Response ◽  
Activated T Cells ◽  
Adaptive Immune

Nowadays the positive immune involvement in the eradication of tumor cells is assigned to the adaptive immune response. By awakening of in vivo responding T cells that are suppressed by the tumor and prevents immunological cure of the cancer. The adaptive immune response is a complex of different cells and protein molecules. Normally activated T cells are well-ordered by several late occurring inhibitors to contain the response to the unknown invaders and spare the normal cells. The tumor strengthens this inhibitory response to escape from immune elimination. Immunotherapy is to unleash the full capacity of the adaptive immune system by blocking this inhibitor response by monoclonal antibodies but with the potential drawback of autoimmune phenomena. Seen the success of the immunotherapy another feature of the immune system is overlooked. Cytokines and chemokines became in oblivion after their suspected necrosis of the tumor (TNF) did not fulfil their initial hope. When patients seek help for their complaints the ovarian cancer is in most cases already metastasized to the peritoneum and omentum. Here, we show that on the one hand chemokines produced by Th2, CD8 and NK cells inhibit cancer spreading and thus leads to a better operability and thus better survival. On the other hand, chemokine receptors are expressed by the tumor that are a decoy by binding chemokines that normally should attract antigen cross-presenting dendritic cells, which start an adaptive T cell response.

scholarly journals Chemokines are Underestimated in Preventing the Metastasizing and The Immune Elimination of Ovarian Cancer

2019 ◽  
pp. 1-4
Author(s):  
Ruurd Torensma ◽  
Petra L.M.Zusterzeel ◽  
Ruurd Torensma
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Chemokine Receptors ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Inhibitory Response ◽  
T Cell Response ◽  
Activated T Cells ◽  
Adaptive Immune

Nowadays the positive immune involvement in the eradication of tumor cells is assigned to the adaptive immune response. By awakening of in vivo responding T cells that are suppressed by the tumor and prevents immunological cure of the cancer. Normally activated T cells are well-ordered by several late occurring inhibitors to contain the response to the unknown invaders and spare the normal cells. The tumor strengthens this inhibitory response to escape from immune elimination. Immunotherapy is to unleash the full capacity of the adaptive immune system by blocking this inhibitor response by monoclonal antibodies but with the potential drawback of autoimmune phenomena. Cytokines and chemokines became in oblivion after their suspected necrosis of the tumor (TNF) did not fulfil their initial hope. Ovarian cancer is in most cases already metastasized to the peritoneum and omentum. Here, we show that on the one hand chemokines produced by Th2, CD8 and NK cells inhibit cancer spreading and thus leads to a better operability and better survival. Chemokine receptors are expressed by the tumor that are a decoy by binding chemokines that normally should attract antigen cross-presenting dendritic cells that start an enforced T cell response to replace the exhausted T cells

scholarly journals Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 3940-3946 ◽  
Author(s):  
Cuixia Shi ◽  
Bikash Sahay ◽  
Jennifer Q. Russell ◽  
Karen A. Fortner ◽  
Nicholas Hardin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Borrelia Burgdorferi ◽  
Adaptive Immune Response ◽  
Γδ T Cells ◽  
Content Type ◽  
Adaptive Immune ◽  
Cytokines And Chemokines

ABSTRACTLittle is known regarding the function of γδ T cells, although they accumulate at sites of inflammation in infections and autoimmune disorders. We previously observed that γδ T cellsin vitroare activated byBorrelia burgdorferiin a TLR2-dependent manner. We now observe that the activated γδ T cells can in turn stimulate dendritic cellsin vitroto produce cytokines and chemokines that are important for the adaptive immune response. This suggested thatin vivoγδ T cells may assist in activating the adaptive immune response. We examined this possibilityin vivoand observed that γδ T cells are activated and expand in number duringBorreliainfection, and this was reduced in the absence of TLR2. Furthermore, in the absence of γδ T cells, there was a significantly blunted response of adaptive immunity, as reflected in reduced expansion of T and B cells and reduced serum levels of anti-Borreliaantibodies, cytokines, and chemokines. This paralleled a greaterBorreliaburden in γδ-deficient mice as well as more cardiac inflammation. These findings are consistent with a model of γδ T cells functioning to promote the adaptive immune response during infection.

scholarly journals Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells

2008 ◽  
Vol 9 (12) ◽  
pp. 1356-1363 ◽  
Author(s):  
Baoli Yang ◽  
Denise L Gay ◽  
Megan K L MacLeod ◽  
Xiao Cao ◽  
Tamara Hala ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Adaptive Immune Response ◽  
Activated T Cells ◽  
Adaptive Immune

scholarly journals Too Much of a Good Thing: High T Cell Count Can Kill Newborns

2019 ◽  
Vol 2 (2) ◽  
pp. 15-16
Author(s):  
Angelina Bustos ◽  
Lai Xu ◽  
Garett Dunsmore ◽  
Shokrollah Elahi
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Cd8 T Cells ◽  
Adaptive Immune Response ◽  
Spleen Cells ◽  
Robust Immune Response ◽  
Adaptive Immune ◽  
Neonatal Immunity ◽  
Low Exposure

Neonates have a weakened immune system that could be due to low exposure to pathogens resulting in low adaptive immunity and/or purposeful immune suppression to protect the weak neonate from a robust immune response. The purpose of this project is to find preliminary data to further investigate why the immune system of neonates are weaker, and to possibly improve neonatal immunity while protecting against a powerful immune response in the future.  Using processed mice spleen cells that were stained for CD4 and CD8 to be subjected to flow cytometry, an increase in the percent of helper CD4 and killer CD8 T cells were observed as the mice aged. This indicates that neonates do have a weaker immune system. Between healthy mice and mice infected with either Bordetella pertussis or Listeria, a decrease in the percent of CD4 and CD8 T cells were found, which could be because not enough time had passed for an adaptive immune response.

scholarly journals Regulation of peripheral T cell activation by calreticulin

2006 ◽  
Vol 203 (2) ◽  
pp. 461-471 ◽  
Author(s):  
Simona Porcellini ◽  
Elisabetta Traggiai ◽  
Ursula Schenk ◽  
Denise Ferrera ◽  
Michela Matteoli ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Adaptive Immune Response ◽  
T Cell Response ◽  
Mitogen Activated Protein Kinase ◽  
Immunodeficient Mice ◽  
Adaptive Immune ◽  
The Impact

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt−/− hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt−/− T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.

scholarly journals Clinical outcomes of prexasertib monotherapy in recurrent BRCA wild-type high-grade serous ovarian cancer involve innate and adaptive immune responses

2020 ◽  
Vol 8 (2) ◽  
pp. e000516
Author(s):  
Erika J Lampert ◽  
Ashley Cimino-Mathews ◽  
Joo Sang Lee ◽  
Jayakumar Nair ◽  
Min-Jung Lee ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
T Cells ◽  
Immune Responses ◽  
Adaptive Immune Response ◽  
Cell Cycle Checkpoint ◽  
High Grade ◽  
Blood Samples ◽  
Adaptive Immune ◽  
Cycle Checkpoint

BackgroundPreclinical data suggest cell cycle checkpoint blockade may induce an immunostimulatory tumor microenvironment. However, it remains elusive whether immunomodulation occurs in the clinical setting. To test this, we used blood and fresh tissue samples collected at baseline and post therapy from a phase II trial of the cell cycle checkpoint 1 inhibitor (CHK1i) prexasertib in recurrent ovarian cancer.MethodsPaired blood samples and fresh core biopsies, taken before treatment was started at baseline (cycle 1 day 1 (C1D1)) and post second dose on day 15 of cycle 1 (C1D15), were collected. To evaluate changes in the immune responses after treatment, multiparametric flow cytometry for DNA damage markers and immune cell subsets was performed on paired blood samples. RNA sequencing (RNAseq) of paired core biopsies was also analyzed. Archival tissue immune microenvironment was evaluated with immunohistochemistry. All correlative study statistical analyses used two-sided significance with a cut-off of p=0.05.ResultsFlow cytometric analysis showed significantly increased γ-H2AX staining after CHK1i treatment, accompanied by increased monocyte populations, suggestive of an activated innate immune response (median 31.6% vs 45.6%, p=0.005). Increased expressions of immunocompetence marker HLA-DR (Human Leukocyte Antigen DR antigen) on monocytes and of TBK1, a marker of STING (stimulator of interferon genes) pathway activation, in biopsies were associated with improved progression-free survival (PFS) (9.25 vs 3.5 months, p=0.019; 9 vs 3 months, p=0.003, respectively). Computational analysis of RNAseq data indicated increased infiltration of tumor niches by naïve B-cells and resting memory T-cells, suggestive of a possibly activated adaptive immune response, and greater T-reg infiltration after treatment correlated with worse PFS (9.25 vs 3.5 months, p=0.007). An immunosuppressive adaptive immune response, perhaps compensatory, was also observed on flow cytometry, including lymphodepletion of total peripheral CD4+ and CD8+T cells after CHK1i and an increase in the proportion of T-regs among these T-cells. Additionally, there was a trend of improved PFS with greater tumor-infiltrating lymphocytes (TILs) in archival tissues (13.7 months >30% TILs vs 5.5 months ≤30% TILs, p=0.05).ConclusionOur study demonstrates that a favorable clinical response in high-grade serous ovarian carcinoma patients treated with CHK1i is possibly associated with enhanced innate and adaptive immunity, requiring further mechanistic studies. It is supportive of current efforts for a clinical development strategy for therapeutic combinations with immunotherapy in ovarian cancer.

scholarly journals Activated adaptive immune system in dissected bicuspid aortic valve aortas: trigger for dissection?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.H.J Staal ◽  
K.R.G Cortenbach ◽  
M.A.J Gorris ◽  
G.S.C Geuzebroek ◽  
L.J Wisse ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Immune System ◽  
Aortic Valve ◽  
Adaptive Immune Response ◽  
Adaptive Immune System ◽  
Helper T Cells ◽  
Funding Source ◽  
Adaptive Immune ◽  
The Media

Abstract Background/Introduction Bicuspid aortic valve (BAV) is associated with ascending aorta aneurysms and dissections. Presently, genetic factors and pathological flow patterns are considered responsible for aneurysm formation in BAV. Despite, indication for preventive surgery is presently only defined by vessel diameter which is poor marker for dissection, as it does not take other processes responsible for the vulnerability of the aorta into account. Purpose Inflammation is not considered a player in BAV aortopathy. We introduce a quantitative immunohistochemistry (IHC) approach to sensitively look at the potential role of both the innate and adaptive immune system in BAV aortopathy. Methods Dilated (n=8), non-dilated (n=14) and dissected (n=4) BAV ascending aortas were collected during surgery or from post-mortem donors. Median time from symptoms to surgery for dissections was just over 4 hours. Tissue was stained with a novel 8-colour IHC technique allowing for simultaneous visualization of 6 markers per slide, completed with DAPI nuclear counter-stain and elastin fiber autofluorescence. One panel focused on the adaptive immune system (identifying B cells and classic dendritic cells type 2 (cDC2s) and phenotyping T cells), and the other on the innate immune system (assessing macrophage polarization and neutrophil extravasation). All cells were identified and comprehensively phenotyped using automated quantitative analysis. Results Aneurysm formation was associated with an organized and consistent increase of lymphocytes in the adventitia. B cell follicles and helper T cell expansion were identified, suggestive of a targeted adaptive immune response (Fig. 1a). Only dissected aortas showed a statistically significant increase of helper T (p=0.3) and cDC2s (p=0.3) in the media, when compared to non-dilated and dilated samples (Fig. 1b). The short time between dissection symptoms and surgery suggests these cells were present before the dissection occurred. Furthermore, aneurysms and dissections are associated with a shift in macrophage phenotype to the more aggressive M1-like subset. In summary, we found that a progression of aggressive immune cells in the adventitia and media was correlated to a progression in disease state; from normal to dilated to dissected. Conclusions Aorta dilatation in patients with BAV is associated with an expansion of B and helper T cells in the adventitial compartment without changes in the media. This result might indicate an antigen-driven adaptive immune response. Only dissections show an increase in helper T cells and cDC2s in the media, together with polarization of macrophages to a more M1-like phenotype. We hypothesize that antigen-specific helper T cells expand in the adventitia, migrate to the media, and then potentiate macrophages which can eventually lead to tissue degeneration. These associations could shine light on the final step in the deterioration of the aorta towards a dissection. Figure 1. Microscopy results Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): TTW-NWO open technology grant (STW-14716), ERC-2014-StG-336454-CoNQUeST

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