scholarly journals Adhesion Molecule Targeted Therapy for Non-Infectious Uveitis

2022 ◽  
Vol 23 (1) ◽  
pp. 503
Author(s):  
Yi-Hsing Chen ◽  
Sue Lightman ◽  
Malihe Eskandarpour ◽  
Virginia L. Calder
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Specific Treatment ◽  
Retinal Tissue ◽  
Inflammatory Eye Disease ◽  
Infectious Uveitis ◽  
Systemic Side Effects ◽  
Immune Cell Migration ◽  
Future Direction

Non-infectious uveitis (NIU) is an inflammatory eye disease initiated via CD4+ T-cell activation and transmigration, resulting in focal retinal tissue damage and visual acuity disturbance. Cell adhesion molecules (CAMs) are activated during the inflammatory process to facilitate the leukocyte recruitment cascade. Our review focused on CAM-targeted therapies in experimental autoimmune uveitis (EAU) and NIU. We concluded that CAM-based therapies have demonstrated benefits for controlling EAU severity with decreases in immune cell migration, especially via ICAM-1/LFA-1 and VCAM-1/VLA-4 (integrin) pathways. P-selectin and E-selectin are more involved specifically in uveitis related to vasculitis. These therapies have potential clinical applications for the development of a more personalized and specific treatment. Localized therapies are the future direction to avoid serious systemic side effects.

scholarly journals Endogenous retrovirus-encoded Syncytin-2 contributes to exosome-mediated immunosuppression of T cells†

2019 ◽  
Author(s):  
Adjimon G Lokossou ◽  
Caroline Toudic ◽  
Phuong Trang Nguyen ◽  
Xavier Elisseeff ◽  
Amandine Vargas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Map Kinases ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Endogenous Retrovirus ◽  
Jurkat Cells ◽  
Peripheral Blood Mononuclear ◽  
Interfering Rna

Abstract Modulation of the activation status of immune cell populations during pregnancy depends on placental villous cytotrophoblast (VCT) cells and the syncytiotrophoblast (STB). Failure in the establishment of this immunoregulatory function leads to pregnancy complications. Our laboratory has been studying Syncytin-2 (Syn-2), an endogenous retroviral protein expressed in placenta and on the surface of placental exosomes. This protein plays an important role not only in STB formation through its fusogenic properties, but also through its immunosuppressive domain (ISD). Considering that Syn-2 expression is importantly reduced in preeclamptic placentas, we were interested in addressing its possible immunoregulatory effects on T cells. Activated Jurkat T cells and peripheral blood mononuclear cells (PBMCs) were treated with monomeric or dimerized version of a control or a Syn-2 ISD peptide. Change in phosphorylation levels of ERK1/2 MAP kinases was selectively noted in Jurkat cells treated with the dimerized ISD peptide. Upon incubation with the dimerized Syn-2 ISD peptide, significant reduction in Th1 cytokine production was further demonstrated by ELISA and Human Th1/Th2 Panel Multi-Analyte Flow Assay. To determine if exosome-associated Syn-2 could also be immunosuppressive placental exosomes were incubated with activated Jurkat and PBMCs. Quantification of Th1 cytokines in the supernatants revealed severe reduction in T cell activation. Interestingly, exosomes from Syn-2-silenced VCT incubated with PBMCs were less suppressive when compared with exosome derived from VCT transfected with control small interfering RNA (siRNA). Our results suggest that Syn-2 is an important immune regulator both locally and systemically, via its association with placental exosomes.

Altered immune cell profiles and impaired CD4 T cell activation in single and multi‐food allergic adolescents

2021 ◽  
Author(s):  
Melanie R. Neeland ◽  
Sandra Andorf ◽  
Thanh D. Dang ◽  
Vicki L. McWilliam ◽  
Kirsten P. Perrett ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Cd4 T Cell

scholarly journals Prognostic and predictive value of FCER1G in glioma outcomes and response to immunotherapy

2021 ◽  
Author(s):  
Houshi Xu ◽  
Qingwei Zhu ◽  
Lan Tang ◽  
Junkun Jiang ◽  
Huiwen Yuan ◽  
...  
Keyword(s):  
T Cell Activation ◽  
Predictive Value ◽  
Cell Activation ◽  
Immune Cell ◽  
Cox Regression ◽  
Glioma Patient ◽  
Clinical Prognosis ◽  
Multiple Factors ◽  
Dismal Prognosis ◽  
Geo Database

Abstract Purpose: Glioma is the most prevalent malignant form of brain tumors, with a dismal prognosis. Currently, cancer immunotherapy has emerged as a revolutionary treatment for patients with advanced highly aggressive therapy-resistant tumors. However, there is no effective biomarker to reflect the response to immunotherapy in glioma patient so far. So we aim to assess the clinical predictive value of FCER1G in patients with glioma. Methods: The expression level and correlation between clinical prognosis and FER1G levels were analyzed with the data from CGGA, TCGA, and GEO database. Univariate and multivariate cox regression model was built to predict the prognosis of glioma patients with multiple factors. Then the correlation between FCER1G with immune cell infiltration and activation was analyzed. At last, we predict the immunotherapeutic response in both high and low FCER1G expression subgroups.Results: FCER1G was significantly higher in glioma with greater malignancy and predicted poor prognosis. In multivariate analysis, the hazard ratio of FCER1G expression (Low versus High) was 0.66 and 95% CI is 0.54 to 0.79 (P <0.001), whereas age (HR=1.26, 95% CI=1.04-1.52), grade (HR=2.75, 95% CI=2.06-3.68), tumor recurrence (HR=2.17, 95% CI=1.81-2.62), IDH mutant (HR=2.46, 95% CI=1.97-3.01) and chemotherapeutic status (HR=1.4, 95% CI=1.20-1.80) are also included. Furthermore, we illustrated that gene FCER1G stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes and T cell activation. At last, we demonstrated that high FCER1G levels presented great immunotherapeutic response in glioma patients.Conclusions: This study demonstrated FCER1G as a novel predictor for clinical diagnosis, prognosis, and response to immunotherapy in glioma patient. Assess expression of FCER1G is a promising method to discover patients that may benefit from immunotherapy.

IMMU-04. UNVEILING THE TUMOR-METABOLOME-IMMUNITY AXIS OF GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi92-vi92
Author(s):  
Mirco Friedrich ◽  
Lukas Bunse ◽  
Roman Sankowski ◽  
Wolfgang Wick ◽  
Marco Prinz ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Myeloid Cell ◽  
Tumor Evolution ◽  
Large Neutral Amino Acid ◽  
Immune Microenvironment ◽  
Idh Mutations

Abstract The glioma microenvironment orchestrates tumor evolution, progression, and resistance to therapy. In high-grade gliomas, microglia and monocyte-derived macrophages constitute up to 70% of the tumor mass. However, the dynamics and phenotypes of intratumoral myeloid cells during tumor progression are poorly understood. Here we define myeloid cellular states in gliomas by longitudinal single-cell profiling and demonstrate their strict control by the tumor genotype. We report the unexpected and clinically highly relevant finding that human as well as murine gliomas with Isocitrate Dehydrogenase (IDH)1-R132H, a key oncogenic driver mutation of glioma, subdue their innate immune microenvironment by prompting a multifaceted reprogramming of myeloid and T cell metabolism. We employed integrated single-cell transcriptomic, time-of-flight mass cytometry and proteomic analyses of human healthy cortex control and glioma samples to identify myeloid cell subsets with distinct fates in IDH-mutated glioma that diverge from canonical trajectories of antigen-presenting cells as a result of a monocyte-to-macrophage differentiation block. Moving beyond single time point assessments, we now longitudinally describe differential immune cell infiltration and phenotype dynamics during glioma progression that are orchestrated by a fluctuating network of resident microglial cells and educated recruited immune cells. IDH mutations in glioma induce a tolerogenic alignment of their immune microenvironment through increased tryptophan uptake via large neutral amino acid transporter (LAT1)-CD98 and subsequent activation of the aryl hydrocarbon receptor (AHR) in educated blood-borne macrophages. In experimental tumor models, this immunosuppressive phenotype was reverted by LAT1-CD98 and AHR inhibitors. Taken together with direct effects on T cell activation, our findings not only link this oncogenic metabolic pathway to distinct immunosuppressive pathways but also provide the rationale and novel molecular targets for the development of immunotherapeutic concepts addressing the disease-defining microenvironmental effects of IDH mutations.

IMMU-13. COMBINED MODULATION OF THE TGF-Β PATHWAY AND GITR IMMUNE CHECKPOINT SIGNALING PROMOTES ANTI-TUMOR IMMUNITY IN SYNGENEIC GLIOMA MODELS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi94-vi94
Author(s):  
Daniela Lorizio ◽  
Michael Weller ◽  
Manuela Silginer ◽  
Alan Epstein ◽  
Patrick Roth
Keyword(s):  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Immune Cell ◽  
Single Agent ◽  
Underlying Mechanism ◽  
T Effector Cells ◽  
Promising Therapeutic Approach

Abstract The profound local immunosuppressive microenvironment is one hallmark of glioblastoma, which results in resistance to most immunotherapeutic strategies that have been explored so far. Reverting this condition in order to reinvigorate anti-glioma immunity might be a promising therapeutic approach. Transforming growth factor (TGF)-β signaling is deregulated in different cancer types and contributes to the malignant phenotype of glioma cells. Glioma-derived TGF-β is also a major immunosuppressive factor in the tumor microenvironment. Furthermore, intratumoral regulatory T (Treg) cells and activated T effector cells express high levels of the co-stimulatory immune checkpoint glucocorticoid-induced tumor necrosis factor receptor (GITR). Agonistic anti-GITR antibodies have been explored in preclinical tumor models and are under investigation in clinical trials for the treatment of solid tumors. We evaluated the effect of TGF-β and GITR targeting on anti-tumor immune responses in syngeneic mouse glioma models. In co-culture settings, GITR modulation with a GITR ligand (GITRL)-Fc fusion protein, given alone or in combination with a pharmacological TGF-β receptor inhibitor, led to increased T cell activation. Furthermore, the combined targeting of the two pathways resulted in significantly higher immune cell-mediated tumor cell killing than either treatment alone. In vivo, TGF-β inhibition and GITR signaling modulation resulted in a higher fraction of long-term surviving glioma-bearing mice than single-agent treatment. Surviving mice were resistant to tumor re-challenge, suggesting adaptive immunity as an underlying mechanism. These data support the assumption that combined immunotherapeutic strategies may represent a promising approach for the treatment of glioma.

scholarly journals T Cell Activation Machinery: Form and Function in Natural and Engineered Immune Receptors

2020 ◽  
Vol 21 (19) ◽  
pp. 7424
Author(s):  
Nicholas J. Chandler ◽  
Melissa J. Call ◽  
Matthew E. Call
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Immune Cell ◽  
Single Chain ◽  
Design Work ◽  
Cell Therapies ◽  
Form And Function ◽  
Car T ◽  
And Function

The impressive success of chimeric antigen receptor (CAR)-T cell therapies in treating advanced B-cell malignancies has spurred a frenzy of activity aimed at developing CAR-T therapies for other cancers, particularly solid tumors, and optimizing engineered T cells for maximum clinical benefit in many different disease contexts. A rapidly growing body of design work is examining every modular component of traditional single-chain CARs as well as expanding out into many new and innovative engineered immunoreceptor designs that depart from this template. New approaches to immune cell and receptor engineering are being reported with rapidly increasing frequency, and many recent high-quality reviews (including one in this special issue) provide comprehensive coverage of the history and current state of the art in CAR-T and related cellular immunotherapies. In this review, we step back to examine our current understanding of the structure-function relationships in natural and engineered lymphocyte-activating receptors, with an eye towards evaluating how well the current-generation CAR designs recapitulate the most desirable features of their natural counterparts. We identify key areas that we believe are under-studied and therefore represent opportunities to further improve our grasp of form and function in natural and engineered receptors and to rationally design better therapeutics.

scholarly journals ITPKC as a Prognostic and Predictive Biomarker of Neoadjuvant Chemotherapy for Triple Negative Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2758 ◽  
Author(s):  
Masanori Oshi ◽  
Stephanie Newman ◽  
Vijayashree Murthy ◽  
Yoshihisa Tokumaru ◽  
Li Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
T Cell Activation ◽  
Triple Negative Breast Cancer ◽  
Cell Activation ◽  
Triple Negative ◽  
Immune Cell ◽  
Tumor Infiltrating Lymphocytes ◽  
Predictive Biomarker ◽  
Negative Regulator

Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with higher mortality than the others. Pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) is considered as a surrogate to predict survival. Inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is a negative regulator of T cell activation, and reduction in ITPKC function is known to promote Kawasaki disease. Given the role of tumor infiltrating lymphocytes in NAC and since TNBC has the most abundant immune cell infiltration in breast cancer, we hypothesized that the ITPKC expression level is associated with NAC response and prognosis in TNBC. The ITPKC gene was expressed in the mammary gland, but its expression was highest in breast cancer cells among other stromal cells in a bulk tumor. ITPKC expression was highest in TNBC, associated with its survival, and was its independent prognostic factor. Although high ITPKC was not associated with immune function nor with any immune cell fraction, low ITPKC significantly enriched cell proliferation-related gene sets in TNBC. TNBC with low ITPKC achieved a significantly higher pCR rate after NAC. To the best of our knowledge, this is the first report to demonstrate that ITPKC gene expression may be useful as a prognostic and predictive biomarker in TNBC.

scholarly journals IMMU-46. EXAMINATION OF THE EFFECTS OF DEXAMETHASONE ON THE EFFICACY OF IMMUNOTHERAPY IN GLIOMA USING GENE-MEDIATED CYTOTOXIC IMMUNOTHERAPY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi129-vi129
Author(s):  
Marilin Koch ◽  
Mykola Zdioruk ◽  
M Oskar Nowicki ◽  
Estuardo Aguilar ◽  
Laura Aguilar ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Symptomatic Treatment ◽  
Tumor Cell Death ◽  
The Impact

Abstract RATIONALE Dexamethasone is frequently used in symptomatic treatment of glioma patients, although it is known to cause immune suppression. Checkpoint inhibitor immunotherapies have not yet been successful in glioma treatments. Gene-mediated cytotoxic immunotherapy (GMCI) is an immunotherapeutic approach that uses aglatimagene besadenovec with an anti-herpetic prodrug to induce immunogenic tumor cell death and immune cell attraction to the tumor site with potent CD8 T cell activation. GMCI is currently in clinical trials for solid tumors including glioblastoma, where it showed encouraging survival results in a Phase 2 study that did not limit the use of dexamethasone. However, the effects of dexamethasone on its efficacy have not been explored. METHODS We investigated the effects of dexamethasone on GMCI in vitro using cytotoxicity and T-cell-killing assays in glioblastoma cell lines. The impact of dexamethasone in vivo was assessed in an orthotopic syngeneic murine glioblastoma model. RESULTS Cyotoxicity assays showed that Dexamethasone has a slight impact on GMCI in vitro. In contrast, we observed a highly significant effect in T-cell-functional assays in which killing was greatly impaired. Immune cell response assays revealed a reduced T-cell proliferation after co-culture with supernatant from dexamethasone or combination treated glioblastoma cells in contrast to GMCI alone. In a murine model, the combination of GMCI and dexamethasone resulted in a significant reduction in median symptom-free survival (29d) in comparison to GMCI alone (39.5d) (P = 0.0184). CONCLUSION Our data suggest that high doses of dexamethasone may negatively impact the efficacy of immunotherapy for glioma, which may be a consequence of impaired T cell function. These results support the idea that there is a need in identifying possible alternatives to dexamethasone to maximize the effectiveness of immunostimulatory therapies such as GMCI.

scholarly journals GABAA receptor α4-subunit knockout enhances lung inflammation and airway reactivity in a murine asthma model

2017 ◽  
Vol 313 (2) ◽  
pp. L406-L415 ◽  
Author(s):  
Gene T. Yocum ◽  
Damian L. Turner ◽  
Jennifer Danielsson ◽  
Matthew B. Barajas ◽  
Yi Zhang ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Immune Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Therapeutic Potential ◽  
Ex Vivo ◽  
Asthma Model

Emerging evidence indicates that hypnotic anesthetics affect immune function. Many anesthetics potentiate γ-aminobutyric acid A receptor (GABAAR) activation, and these receptors are expressed on multiple subtypes of immune cells, providing a potential mechanistic link. Like immune cells, airway smooth muscle (ASM) cells also express GABAARs, particularly isoforms containing α4-subunits, and activation of these receptors leads to ASM relaxation. We sought to determine if GABAAR signaling modulates the ASM contractile and inflammatory phenotype of a murine allergic asthma model utilizing GABAAR α4-subunit global knockout (KO; Gabra40/0) mice. Wild-type (WT) and Gabra4 KO mice were sensitized with house dust mite (HDM) antigen or exposed to PBS intranasally 5 days/wk for 3 wk. Ex vivo tracheal rings from HDM-sensitized WT and Gabra4 KO mice exhibited similar magnitudes of acetylcholine-induced contractile force and isoproterenol-induced relaxation ( P = not significant; n = 4). In contrast, in vivo airway resistance (flexiVent) was significantly increased in Gabra4 KO mice ( P < 0.05, n = 8). Moreover, the Gabra4 KO mice demonstrated increased eosinophilic lung infiltration ( P < 0.05; n = 4) and increased markers of lung T-cell activation/memory (CD62L low, CD44 high; P < 0.01, n = 4). In vitro, Gabra4 KO CD4+ cells produced increased cytokines and exhibited increased proliferation after stimulation of the T-cell receptor as compared with WT CD4+ cells. These data suggest that the GABAAR α4-subunit plays a role in immune cell function during allergic lung sensitization. Thus GABAAR α4-subunit-specific agonists have the therapeutic potential to treat asthma via two mechanisms: direct ASM relaxation and inhibition of airway inflammation.

Induction of antigen specific CD8+ T cell infiltration by a novel neoadjuvant vaccine containing HSP70 and GPC3 peptides plus soluble LAG-3 and Poly-IC:LC: Interim results of a Phase I study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14306-e14306
Author(s):  
Yukio Tokumitsu ◽  
Shoichi Hazama ◽  
Shun Doi ◽  
Koji Tamada ◽  
Keiko Udaka ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
T Cell Activation ◽  
Phase I Study ◽  
Cell Activation ◽  
Immune Cell ◽  
Antigen Expression ◽  
Lymphocytic Infiltration ◽  
Cell Infiltration ◽  
Novel Therapeutic

e14306 Background: Even with curative resection, the recurrence rate of HCC is still high, and no effective adjuvant therapy is currently available. Our previous Phase I study with novel therapeutic peptides and immune adjuvants demonstrated the safety, antigen specific CTL induction in PBMC and a sign of efficacy (ASCO 2017 Abstract # 3086); thus, we started Phase I study of the same therapy as a perioperative immunotherapy setting in patients with resectable HCC (UMIN000029991). Methods: Two mg each of HLA-A*24:02, 02:01, or 02:06 restricted HSP70- and GPC3-derived peptides, in combination with hLAG-3Ig (1.0 mg) + Poly-IC:LC (1.4 mg) were injected intradermally at four sites of the inguinal and axillary regions every week for 6 weeks before surgery. Patients subsequently received 10 injections of adjuvant immunotherapy over 4 months. Surgical specimens and PBMCs were analyzed by mass cytometry (CyTOF), using 66 antibodies to monitor T cell exhaustion, T cell activation, Effector Treg induction, etc. Tumor specimens were also subjected to immunohistochemical staining of CD3, CD8, PD1, HSP70, and GPC3. The reason for early reporting is the interesting findings at the foci of HCC, and the interim analyses was approved by the Data and Safety Monitoring Committee. Results: Of the 11 screened patients, 5 completed the treatments and were analyzed. We found massive CD8+ T lymphocyte infiltration in the intratumor foci of HCC, which is usually accompanied by peritumoral lymphocytic infiltration. Moreover, the density of lymphocytes was markedly higher in areas of HSP70 or GPC3 antigen expression. One case out of five recurred 5 month after surgery and it showed low CD8+ and PD1+ cell infiltration and high effector Treg (CD4+/CD25+/CD45RA-/FoxP3 +) infiltration. This trend was not observed in PBMC, suggesting the importance of TIL analysis. The high PD1 expression was accompanied by massive intratumoral infiltration of CD8+ lymphocytes. Conclusions: The novel therapeutic peptide and immune adjuvant combination induced sustained immune cell infiltration into tumor microenvironments, especially those presenting target tumor-associated antigens. Our novel immunotherapy may convert cold tumors into hot tumors containing PD1+ lymphocytes. Thus, the combination of this novel strategy with PD (L) 1 antibody is warranted. Clinical trial information: 000029991.

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