Preoperative checkpoint inhibition (CPI) and cryoablation (Cryo) in women with early-stage breast cancer (ESBC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 592-592 ◽  
Author(s):  
Elizabeth Anne Comen ◽  
Yolanda Bryce ◽  
David B. Page ◽  
Stephen Barnett Solomon ◽  
Micaela Rodine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Early Stage ◽  
Checkpoint Inhibition ◽  
Activation Markers ◽  
Immune Correlates ◽  
Immune Biomarkers ◽  
The Impact

592 Background: Checkpoint inhibition (CPI) combined with local strategies that cause local tumor destruction, such as cryo may augment tumor specific immunity and improve survival. We previously demonstrated in 18 ESBC patients (pts) that pre-operative (pre-op) cryo with ipilimumab (ipi) is not only safe but also generates robust local and systemic immune responses (NCT01502592). Given the added activity of dual CPI in other tumors, we undertook a second pilot study of pre-op ipi/nivolumab (nivo)/cryo to confirm the safety of this combination and the impact on immune biomarkers. Methods: In both pilot studies, eligible pts had operable ≥1.5cm invasive HER2 negative ESBC. CPI was administered 8-15d prior to, and cryo was performed 7-10d prior to, standard-of-care (SOC) surgery. Toxicity evaluation continued for 12wks after drug administration. Blood for immune correlates was obtained at baseline, cryo, surgery and 2-4 weeks thereafter. Tumor samples were obtained at cryo and surgery. Flow-cytometry of peripheral lymphocytes was compared to previously reported ipi/cryo responses. Results: After a median follow-up of 66 months all 18 ESBC ipi/cryo pts, including 3 TNBC pts, are recurrence free. In the ipi/nivo/cryo study, the safety primary endpoint was met when 5 pts underwent SOC surgery without delay. Ipi/nivo/cryo was well tolerated overall. One pt on an aromatase inhibitor had grade 4 liver toxicity 8 weeks after surgery. One pt, 3 weeks after her SOC surgery, developed grade 1 hyperthyroidism, preventing a secondary axillary dissection from proceeding as scheduled. Robust activation of peripheral CD4+ and CD8+ T cells peaked at week 2 post ipi/nivo with the majority of activated CD8+ T cells expressing PD1. Comparing the correlatives of the ipi/nivo/cryo study with the prior ipi/cryo study, we observed higher expression of activation markers (Ki-67, ICOS, CTLA-4, LAG-3) on peripheral T cells and downregulation of suppressor cells. Conclusions: Ipi/cryo-treated pts, including 3 TNBC pts, remain recurrence free after > 5y. Combining cryo with ipi/nivo preop is feasible, safe, and associated with greater T cell activation than ipi/cryo alone. These results informed an ongoing randomized phase 2 study of pre-op ipi/nivo/cryo versus SOC in women with residual TNBC after neoadjuvant chemotherapy (NCT03546686). Clinical trial information: NCT02833233.

scholarly journals Immune Suppressive Effects of Plasma-Derived Exosome Populations in Head and Neck Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1997 ◽  
Author(s):  
Inga J. Beccard ◽  
Linda Hofmann ◽  
Jan C. Schroeder ◽  
Sonja Ludwig ◽  
Simon Laban ◽  
...  
Keyword(s):  
T Cells ◽  
Head And Neck ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Suppression ◽  
Cell Activation ◽  
Disease Stage ◽  
High Stage ◽  
Treg Differentiation ◽  
The Impact

Plasma-derived exosomes of head and neck squamous cell carcinoma (HNSCC) patients carry inhibitory factors mediating immune suppression. Separation of tumor-derived exosomes (TEX) and non-TEX may assist in a better understanding of their respective parental cells. Here, we evaluate the impact of TEX or hematopoietic-derived exosomes on immune suppression. We evaluated apoptosis in CD8+ T cells, conversion of CD4+ T cells to regulatory T cells (Treg), and adenosine production by TEX, non-TEX, or total exosomes. Exosome protein cargo was significantly higher in total and CD45(−) exosomes from high stage compared to low stage patients. Furthermore, total and CD45(−) exosomes of high stage patients induced more apoptosis in CD8+ T cells than their low stage counterparts. CD69 suppression, a marker of reduced CD8+ T cell activation, was only mediated by CD45(−) exosomes. All fractions induced Treg differentiation, defined by CD39 expression, but only CD45(−) exosomes showed a stage-dependent conversion. CD45(−) exosomes produced higher adenosine concentrations than CD45(+) exosomes, concluding that adenosine production measured in total exosomes mainly derives from TEX. The presented results show significant induction of immune suppression by TEX in HNSCC. This immunosuppressive effect supports the potential role of exosomes as liquid biomarkers for disease stage and level of immune suppression.

Abstract P167: Title: Prediction of Arterial Stiffness from Early T-cell Activation among HIV and HCV Co-infected Women in the Women's Interagency HIV Study (WIHS)

Circulation ◽  
2012 ◽  
Vol 125 (suppl_10) ◽  
Author(s):  
Roksana Karim ◽  
Naoko Kono ◽  
Robert Kaplan ◽  
Wendy J Mack ◽  
Howard N Hodis ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Arterial Stiffness ◽  
Hiv Infection ◽  
T Cell Activation ◽  
Cell Activation ◽  
Infection Status ◽  
Activation Markers ◽  
Color Flow ◽  
The Impact

Introduction: Activation of T-lymphocytes, a hallmark of HIV infection, reaches a set point early in HIV infection and persists even after viral suppression with highly active antiretroviral therapy (HAART). Early T-cell activation predicts subsequent CD4 depletion, progression to AIDS and survival. HIV-infected subjects are at high risk for premature atherosclerosis. Little is known regarding the impact of early T cell activation on arterial stiffness. While Kaplan et al. (2011) were the first and only group to show a cross-sectional association, we investigate here if early T cell activation can predict future arterial stiffness. Hypothesis: High early T cell activation will predict increased arterial stiffness, measured 5.5 (IQR=2.5-7.5) years later, in HIV and HCV co-infected women. Methods: A longitudinal study nested within the WIHS, an ongoing prospective cohort study. Percentages of CD4 and CD8 T cell activation, assessed by CD38 and HLA-DR co-expression using 3-color flow cytometry, were measured on average 5.5 years before arterial stiffness assessments (carotid artery distensibility, and Young’s elastic modulus for elasticity) using B-mode carotid ultrasound. Multiple linear regression models evaluated the association between log-transformed T cell activation markers (independent variables) and arterial stiffness (dependent variable). Analyses were stratified by HCV co-infection status and by pre- and post-HAART assessment of T cell activation. Results: A total of 376 HIV+ women (185 HCV+) were included in the analysis. Participants were on average 46(SD=9) years old, 59% Black, and 49% were current smokers. Activation of both CD4 and CD8 T cells significantly univariately predicted reduced distensibility and elasticity among HIV-infected women. CD4 activation continued to significantly predict distensibility (β(SEM)= −3.51(1.30) 10 −6* N −1* m 2 , p=0.01), and elasticity (0.11(0.04)10 5* N * m 2 , p=0.004) with adjustment for age, race, BMI, smoking, ART, CD4 count, and HIV RNA. CD8 activation was no longer associated after adjustment. When stratified by HCV co-infection status, the prediction of arterial stiffness parameters from early CD4 activation was somewhat stronger among the HIV+/HCV+ women compared to HIV+/HCV- women (β(SEM)= −4.44(1.93), p=0.02 vs. −3.04(1.84), p=0.10 for distensibility, and 0.17(0.06), p=0.003 vs. 0.09(0.05), p=0.09 for elasticity); however the test for interaction was not statistically significant. In a subset of 188 women, CD4 activation measured both pre- and post-HAART significantly predicted later arterial stiffness. Conclusions: CD4 activation level predicts future arterial stiffness in HIV-infected women, perhaps more markedly among HCV co-infected women. These data confirm the proinflammatory impact of activated T cells that can cause vascular dysfunction and shed light on the early onset of atherogenesis.

scholarly journals CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3818-3823 ◽  
Author(s):  
Luca Gattinoni ◽  
Anju Ranganathan ◽  
Deborah R. Surman ◽  
Douglas C. Palmer ◽  
Paul A. Antony ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Peripheral Tolerance ◽  
The Impact

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.

Impact of hypoxia on immune cells in human atherosclerotic plaques

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Vorobyeva ◽  
A Lebedeva ◽  
A Elizarova ◽  
E Maryukhnich ◽  
V Gontarenko ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Ex Vivo ◽  
Atherosclerotic Plaques ◽  
Funding Source ◽  
Ex Vivo Model ◽  
Activation Markers ◽  
Hypoxic Conditions ◽  
The Impact

Abstract Background Inflammation plays a major role in atherosclerotic plaques' progression and was shown to be associated with the formation of hypoxic areas within the plaques. However, the data about the impact of hypoxia on atherosclerosis are contradictory, in part due to inadequacy of in vitro and animal models to reproduce faithfully the complexity of human atherosclerotic plaques. Purpose The aim of this study was to investigate the effect of hypoxia on immune status in the ex vivo system of human atherosclerotic plaques. Methods We collected 25 atherosclerotic plaques from patients undergoing carotid endarterectomy, cut plaques into ring-shaped slices and cultured them for 24 hours at the liquid/air interface on collagen sponges under hypoxic (2% O2) and normoxic (12% O2) conditions. After 24 hours we evaluated T-cell activation status within plaques according to the presence of membrane activation markers by means of multiparametric flow cytometry and the activity of cytokine production using xMAP technology. Results We found that CD8 T cells from human atherosclerotic plaques cultured under hypoxic conditions compared to normoxic conditions have a decreased expression of CD69 activation marker (42.7 [34.3; 50.9]% vs 53.8 [33.3; 63.3]%, n=10, p=0.047) and lower level of CD69 and HLA-DR coexpression (16.0 [10.5; 22.3] vs 22.6 [11.3; 28.2], n=10, p=0.02). CD4 T cells did not show any significant changes in expression of activation markers under hypoxia. Hypoxic conditions also resulted in a reduced IL-10 production (104.2 [53.8; 170.9] vs 235.2 [158.5; 335.3] pg/100 mg of tissue, n=20, p=0.0001) and increased VEGF production (116.1 [79.8; 253.5] vs 89.9 [71.1; 148.8] pg/100 mg of tissue, n=20, p=0.033). Conclusions Our results indicate that hypoxia causes a decrease in the activity of cytotoxic T cells and increases stimuli for angiogenesis within the human atherosclerotic plaques. The established ex vivo model of human atherosclerotic plaques culture under hypoxia enables further studies of the hypoxia impact on atherosclerosis. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Russian Science Foundation grant

scholarly journals Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19

2021 ◽  
Vol 6 (57) ◽  
pp. eabf7570
Author(s):  
Laura A. Vella ◽  
Josephine R. Giles ◽  
Amy E. Baxter ◽  
Derek A. Oldridge ◽  
Caroline Diorio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Cell Activation ◽  
Vascular Complications ◽  
Adult Disease ◽  
Vasoactive Medication ◽  
Inflammatory Syndrome

Pediatric COVID-19 following SARS-CoV-2 infection is associated with fewer hospitalizations and often milder disease than in adults. A subset of children, however, present with Multisystem Inflammatory Syndrome in Children (MIS-C) that can lead to vascular complications and shock, but rarely death. The immune features of MIS-C compared to pediatric COVID-19 or adult disease remain poorly understood. We analyzed peripheral blood immune responses in hospitalized SARS-CoV-2 infected pediatric patients (pediatric COVID-19) and patients with MIS-C. MIS-C patients had patterns of T cell-biased lymphopenia and T cell activation similar to severely ill adults, and all patients with MIS-C had SARS-CoV-2 spike-specific antibodies at admission. A distinct feature of MIS-C patients was robust activation of vascular patrolling CX3CR1+ CD8+ T cells that correlated with the use of vasoactive medication. Finally, whereas pediatric COVID-19 patients with acute respiratory distress syndrome (ARDS) had sustained immune activation, MIS-C patients displayed clinical improvement over time, concomitant with decreasing immune activation. Thus, non-MIS-C versus MIS-C SARS-CoV-2 associated illnesses are characterized by divergent immune signatures that are temporally distinct from one another and implicate CD8+ T cells in the clinical presentation and trajectory of MIS-C.

scholarly journals EXTH-43. GENERATION OF A B-CELL-BASED VACCINE FOR THE TREATMENT OF GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii96-ii96
Author(s):  
Catalina Lee Chang ◽  
Jason Miska ◽  
David Hou ◽  
Aida Rashidi ◽  
Peng Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Cross Presentation ◽  
Control Tumor Growth ◽  
Efficient Alternative ◽  
Control Tumor ◽  
Secondary Lymphoid Organs

Abstract Immunotherapy has revolutionized the treatment of many tumors. However, most glioblastoma (GBM) patients have not, so far, benefited from such successes. With the goal of exploring ways to boost anti-GBM immunity, we developed a B-cell-based vaccine (BVax) that consists of 4-1BBL+ B cells activated with CD40 agonism and IFNg stimulation. BVaxmigrate to key secondary lymphoid organs and are proficient at antigen cross-presentation, which promotes both the survival and functionality of CD8+ T cells. A combination of radiation, BVax, and PD-L1 blockade conferred tumor eradication in 80% of treated tumor-bearing animals. This treatment elicited immunologic memory that prevented the growth of new tumors upon subsequent re-injection in cured mice. GBM patient-derived BVax were successful in activating autologous CD8+ T cells; these T cells showed a strong ability to kill autologous glioma cells. In addition to the role in activating CD8+ T cells, BVax produce tumor-specific antibodies able to control tumor growth via antibody-mediated cell cytotoxicity. In conclusion, BVax tackles GBM immunosurveillance escape by using both cellular (CD8+ T-cell activation) and humoral (anti-tumor antibody production) immunity. Our study provides an efficient alternative to current immunotherapeutic approaches that can be readily translated to the clinic.

scholarly journals Selective Bystander Proliferation of Memory CD4+ and CD8+ T Cells Upon NK T or T Cell Activation

2000 ◽  
Vol 165 (8) ◽  
pp. 4305-4311 ◽  
Author(s):  
Gérard Eberl ◽  
Pierre Brawand ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation

scholarly journals CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

Blood ◽  
2009 ◽  
Vol 114 (3) ◽  
pp. 580-588 ◽  
Author(s):  
Kathrin Gollmer ◽  
François Asperti-Boursin ◽  
Yoshihiko Tanaka ◽  
Klaus Okkenhaug ◽  
Bart Vanhaesebroeck ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Early Time ◽  
Cell Receptor ◽  
Tcr Signaling ◽  
Activation Markers

Abstract CD4+ T cells use the chemokine receptor CCR7 to home to and migrate within lymphoid tissue, where T-cell activation takes place. Using primary T-cell receptor (TCR)–transgenic (tg) CD4+ T cells, we explored the effect of CCR7 ligands, in particular CCL21, on T-cell activation. We found that the presence of CCL21 during early time points strongly increased in vitro T-cell proliferation after TCR stimulation, correlating with increased expression of early activation markers. CCL21 costimulation resulted in increased Ras- and Rac-GTP formation and enhanced phosphorylation of Akt, MEK, and ERK but not p38 or JNK. Kinase-dead PI3KδD910A/D910A or PI3Kγ-deficient TCR-tg CD4+ T cells showed similar responsiveness to CCL21 costimulation as control CD4+ T cells. Conversely, deficiency in the Rac guanine exchange factor DOCK2 significantly impaired CCL21-mediated costimulation in TCR-tg CD4+ T cells, concomitant with impaired Rac- but not Ras-GTP formation. Using lymph node slices for live monitoring of T-cell behavior and activation, we found that G protein-coupled receptor signaling was required for early CD69 expression but not for Ca2+ signaling. Our data suggest that the presence of CCL21 during early TCR signaling lowers the activation threshold through Ras- and Rac-dependent pathways leading to increased ERK phosphorylation.

A Randomized Phase II Trial of Idiotype Vaccination and Adoptive Autologous T-Cell Transfer in Multiple Myeloma patients

Blood ◽  
2021 ◽  
Author(s):  
Muzaffar H Qazilbash ◽  
Neeraj Y Saini ◽  
Cha Soung-chul ◽  
Zhe Wang ◽  
Edward Stadtmauer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Phase Ii Trial ◽  
Ex Vivo ◽  
Vaccine Strategy ◽  
Randomized Phase Ii

We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding anti-myeloma idiotype-keyhole limpet hemocyanin (Id-KLH) vaccine to vaccine-specific co-stimulated T cells. In this randomized, phase II trial, eligible patients received either the control (KLH only) or Id-KLH vaccine, an auto-transplant, vaccine-specific co-stimulated T-cells expanded ex-vivo, and two booster doses of the assigned vaccine. In 36 patients (20 in KLH, 16 in Id-KLH) enrolled, no dose-limiting toxicity was seen in either arm. At last evaluation, 6 (30%) and 8 (50%) had achieved complete remission in KLH-only and Id-KLH, respectively (p=0.22) and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; p=0.32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with KLH-only patients, there was a greater change in IR genes in T-cells in Id-KLH patients relative to baseline. Specifically, upregulation of genes associated with activation, induction of effector function, and generation of memory CD8+ T cells after Id-KLH, but not after KLH control vaccination, was observed. Similarly, responding patients across both arms were associated with upregulation of genes associated with T-cell activation. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of Id-KLH patients analyzed. In conclusion, in this combination immunotherapy approach, we observed a significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies.

scholarly journals Activation Outcomes Induced in Naïve CD8 T-Cells by Macrophages Primed via “Phagocytic” and Nonphagocytic Pathways

2008 ◽  
Vol 19 (2) ◽  
pp. 701-710 ◽  
Author(s):  
Isabel María Olazabal ◽  
Noa Beatriz Martín-Cofreces ◽  
María Mittelbrunn ◽  
Gloria Martínez del Hoyo ◽  
Balbino Alarcón ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
Microtubule Organizing Center ◽  
Antigen Uptake ◽  
Soluble Peptide

The array of phagocytic receptors expressed by macrophages make them very efficient at pathogen clearance, and the phagocytic process links innate with adaptive immunity. Primary macrophages modulate antigen cross-presentation and T-cell activation. We assessed ex vivo the putative role of different phagocytic receptors in immune synapse formation with CD8 naïve T-cells from OT-I transgenic mice and compared this with the administration of antigen as a soluble peptide. Macrophages that have phagocytosed antigen induce T-cell microtubule-organizing center and F-actin cytoskeleton relocalization to the contact site, as well as the recruitment of proximal T-cell receptor signals such as activated Vav1 and PKCθ. At the same doses of loaded antigen (1 μM), “phagocytic” macrophages were more efficient than peptide-antigen–loaded macrophages at forming productive immune synapses with T-cells, as indicated by active T-cell TCR/CD3 conformation, LAT phosphorylation, IL-2 production, and T-cell proliferation. Similar T-cell proliferation efficiency was obtained when low doses of soluble peptide (3–30 nM) were loaded on macrophages. These results suggest that the pathway used for antigen uptake may modulate the antigen density presented on MHC-I, resulting in different signals induced in naïve CD8 T-cells, leading either to CD8 T-cell activation or anergy.

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