20 results on '"Pyzer AR"'
Search Results
2. Insights from a Rapidly Implemented COVID-19 Biobank Using Electronic Consent and Informatics Tools.
- Author
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Higgs EF, Flood BA, Pyzer AR, Rouhani SJ, Trujillo JA, and Gajewski TF
- Subjects
- Humans, Biological Specimen Banks, COVID-19 Testing, Pandemics, Informed Consent, Databases, Factual, COVID-19 epidemiology
- Abstract
Biobanking during the COVID-19 pandemic presented unique challenges regarding patient enrollment, sample collection, and experimental analysis. This report details the ways in which we rapidly overcame those challenges to create a robust database of clinical information and patient samples while maintaining clinician and researcher safety. We developed a pipeline using REDCap (Research Electronic Data Capture) to coordinate electronic informed consent, sample collection, immunological assay execution, and data analysis for biobanking samples from patients with COVID-19. We then integrated immunological assay data with clinical data extracted from the electronic health record to link study parameters with clinical readouts. Of the 193 inpatients who participated in this study, 138 consented electronically and 56 provided paper consent. We collected and banked blood samples to measure circulating cytokines and chemokines, peripheral immune cell composition and activation status, anti-COVID-19 antibodies, and germline gene polymorphisms. In addition, we collected DNA and RNA from nasopharyngeal swabs to assess viral titer and microbiome composition by 16S sequencing. The rapid spread and contagious nature of COVID-19 required special considerations and innovative solutions to biobank samples quickly while protecting researchers and clinicians. Overall, this workflow and computational pipeline allowed for comprehensive immune profiling of 193 inpatients infected with COVID-19, as well as 89 outpatients, 157 patients receiving curbside COVID-19 testing, and 86 healthy controls. We describe a novel electronic framework for biobanking and analyzing patient samples during COVID-19, and present insights and strategies that can be applied more broadly to other biobank studies.
- Published
- 2023
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3. Lymphatic coagulation and neutrophil extracellular traps in lung-draining lymph nodes of COVID-19 decedents.
- Author
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MacDonald ME, Weathered RK, Stewart EC, Magold AI, Mukherjee A, Gurbuxani S, Smith H, McMullen P, Mueller J, Husain AN, Salles CM, Briquez PS, Rouhani SJ, Yu J, Trujillo J, Pyzer AR, Gajewski TF, Sperling AI, Kilarski WW, and Swartz MA
- Subjects
- Mice, Animals, Lung metabolism, DNA metabolism, Lymph Nodes, Extracellular Traps, COVID-19, Thrombosis metabolism
- Abstract
Clinical manifestations of severe COVID-19 include coagulopathies that are exacerbated by the formation of neutrophil extracellular traps (NETs). Here, we report that pulmonary lymphatic vessels, which traffic neutrophils and other immune cells to the lung-draining lymph node (LDLN), can also be blocked by fibrin clots in severe COVID-19. Immunostained tissue sections from COVID-19 decedents revealed widespread lymphatic clotting not only in the lung but also in the LDLN, where the extent of clotting correlated with the presence of abnormal, regressed, or missing germinal centers (GCs). It strongly correlated with the presence of intralymphatic NETs. In mice, tumor necrosis factor α induced intralymphatic fibrin clots; this could be inhibited by DNase I, which degrades NETs. In vitro, TNF-α induced lymphatic endothelial cell upregulation of ICAM-1 and CXCL8, among other neutrophil-recruiting factors, as well as thrombomodulin downregulation; in decedents, lymphatic clotting in LDLNs. In a separate cohort of hospitalized patients, serum levels of Myeloperoxidase-DNA (MPO-DNA, a NET marker) inversely correlated with antiviral antibody titers, but D-dimer levels, indicative of blood thrombosis, did not correlate with either. Patients with high MPO-DNA but low D-dimer levels generated poor antiviral antibody titers. This study introduces lymphatic coagulation in lungs and LDLNs as a clinical manifestation of severe COVID-19 and suggests the involvement of NETosis of lymphatic-trafficking neutrophils. It further suggests that lymphatic clotting may correlate with impaired formation or maintenance of GCs necessary for robust antiviral antibody responses, although further studies are needed to determine whether and how lymphatic coagulation affects adaptive immune responses., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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4. Severe COVID-19 induces autoantibodies against angiotensin II that correlate with blood pressure dysregulation and disease severity.
- Author
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Briquez PS, Rouhani SJ, Yu J, Pyzer AR, Trujillo J, Dugan HL, Stamper CT, Changrob S, Sperling AI, Wilson PC, Gajewski TF, Hubbell JA, and Swartz MA
- Subjects
- Angiotensin II, Autoantibodies, Blood Pressure, Epitopes metabolism, Humans, Peptidyl-Dipeptidase A metabolism, Protein Binding, SARS-CoV-2, Severity of Illness Index, Spike Glycoprotein, Coronavirus, Angiotensin-Converting Enzyme 2, COVID-19
- Abstract
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation, and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme 2 (ACE2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized patients with COVID-19 developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or receptor-binding domain (RBD), to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.
- Published
- 2022
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5. Antibody and T cell responses to COVID-19 vaccination in patients receiving anticancer therapies.
- Author
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Rouhani SJ, Yu J, Olson D, Zha Y, Pezeshk A, Cabanov A, Pyzer AR, Trujillo J, Derman BA, O'Donnell P, Jakubowiak A, Kindler HL, Bestvina C, and Gajewski TF
- Subjects
- Adrenal Insufficiency complications, Antibodies, Viral blood, Antibody Formation, Humans, Immunity, Cellular, Programmed Cell Death 1 Receptor antagonists & inhibitors, SARS-CoV-2, T-Lymphocytes immunology, Vaccination, Vaccines, Synthetic, mRNA Vaccines immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, Neoplasms complications, Neoplasms drug therapy
- Abstract
Background: Patients with cancer were excluded from phase 3 COVID-19 vaccine trials, and the immunogenicity and side effect profiles of these vaccines in this population is not well understood. Patients with cancer can be immunocompromised from chemotherapy, corticosteroids, or the cancer itself, which may affect cellular and/or humoral responses to vaccination. PD-1 is expressed on T effector cells, T follicular helper cells and B cells, leading us to hypothesize that anti-PD-1 immunotherapies may augment antibody or T cell generation after vaccination., Methods: Antibodies to the SARS-CoV-2 receptor binding domain (RBD) and spike protein were assessed in patients with cancer (n=118) and healthy donors (HD, n=22) after 1, 2 or 3 mRNA vaccine doses. CD4
+ and CD8+ T cell reactivity to wild-type (WT) or B.1.617.2 (delta) spike peptides was measured by intracellular cytokine staining., Results: Oncology patients without prior COVID-19 infections receiving immunotherapy (n=36), chemotherapy (n=15), chemoimmunotherapy (n=6), endocrine or targeted therapies (n=6) and those not on active treatment (n=26) had similar RBD and Spike IgG antibody titers to HDs after two vaccinations. Contrary to our hypothesis, PD-1 blockade did not augment antibody titers or T cell responses. Patients receiving B-cell directed therapies (n=14) including anti-CD20 antibodies and multiple myeloma therapies had decreased antibody titers, and 9/14 of these patients were seronegative for RBD antibodies. No differences were observed in WT spike-reactive CD4+ and CD8+ T cell generation between treatment groups. 11/13 evaluable patients seronegative for RBD had a detectable WT spike-reactive CD4+ T cell response. T cells cross-reactive against the B.1.617.2 variant spike peptides were detected in 31/59 participants. Two patients with prior immune checkpoint inhibitor-related adrenal insufficiency had symptomatic hypoadrenalism after vaccination., Conclusions: COVID-19 vaccinations are safe and immunogenic in patients with solid tumors, who developed similar antibody and T cell responses compared with HDs. Patients on B-cell directed therapies may fail to generate RBD antibodies after vaccination and should be considered for prophylactic antibody treatments. Many seronegative patients do develop a T cell response, which may have an anti-viral effect. Patients with pre-existing adrenal insufficiency may need to take stress dose steroids during vaccination to avoid adrenal crisis., Competing Interests: Competing interests: BAD participated in advisory boards for Janssen and Sanofi. PO received research funding/grants from NIH, Boehringer Ingelheim, Merck, Genentech/Roche, AstraZeneca/MedImmunce, Acerta Pharma, Janssen, Seagen, Astellas Pharma, and Bristol-Myers Squibb; consulting fees from Genentech/Roche, Merck, Astellas Pharma, Inc., Seagen, Atheneum Partners, First Word Publications, Health Advances, Janssen, Dedham Group, Pfizer, CLD, Axiom Healthcare Strategies, EMD Serono, IntrinsiQ Specialty Solutions; payment or honoraria from NAMCP, Med Learning Group, and Curio Science; support for meetings/travel from Seagen, Astellas Pharma, Inc., Genentech/Roche, and Janssen; participation in a Data Safety Monitoring Board or Advisory Board for Janssen, Nektar, Dragonfly Therapeutics, G1 Therapeutics; and is a former stockholder of Allergan which was acquired by AbbVie. AJ participated in consulting and advisory boards for AbbVie, Amgen, BMS, GlaxoSmithKline, Janssen, Karyopharm, Sanofi-Aventis. KLH participated in consulting and advisory boards for Deciphera, BMS, Novocure, Seattle Genetics, Inventiva, AstraZeneca, Bluestar Genomics, and has clinical trial support paid to the institution from Bayer, BMS, Constellation, Deciphera, Inhibrx, Aduro, GSK, Harpoon, Polaris, Macrogenics, Seattle Genetics, Vivace, AstraZeneca, Merck, Roche. CMB participated in consulting, advisory board or speakers’ bureaus for AstraZeneca, BMS, CVS, Genetech, Jazz pharmaceuticals, Johnson and Johnson, Novartis, Pfizer, Regeneron/Sanofi, Seattle Genetics, Takeda, Merck and received research funding from AstraZeneca and Bristol Myers Squibb. TFG has participated in consulting or advisory boards for Merck, Jounce, Fog Pharma, Adaptimmune, Pyxis, Allogene, Catalym, Bicara, Maia, Samyang; has received research support from BMS, Merck, Seattle Genetics, Evelo, Bayer, Pyxis; has licensing or intellectual property agreements with Aduro, Evelo, and BMS; and is a cofounder or shareholder in Jounce and Pyxis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)- Published
- 2022
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6. Severe COVID-19 infection is associated with aberrant cytokine production by infected lung epithelial cells rather than by systemic immune dysfunction.
- Author
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Rouhani SJ, Trujillo JA, Pyzer AR, Yu J, Fessler J, Cabanov A, Higgs EF, Cron KR, Zha Y, Lu Y, Bloodworth JC, Abasiyanik MF, Okrah S, Flood BA, Hatogai K, Leung MY, Pezeshk A, Kozloff L, Reschke R, Strohbehn GW, Chervin CS, Kumar M, Schrantz S, Madariaga ML, Beavis KG, Yeo KJ, Sweis RF, Segal J, Tay S, Izumchenko E, Mueller J, Chen LS, and Gajewski TF
- Abstract
The mechanisms explaining progression to severe COVID-19 remain poorly understood. It has been proposed that immune system dysregulation/over-stimulation may be implicated, but it is not clear how such processes would lead to respiratory failure. We performed comprehensive multiparameter immune monitoring in a tightly controlled cohort of 128 COVID-19 patients, and used the ratio of oxygen saturation to fraction of inspired oxygen (SpO2 / FiO2) as a physiologic measure of disease severity. Machine learning algorithms integrating 139 parameters identified IL-6 and CCL2 as two factors predictive of severe disease, consistent with the therapeutic benefit observed with anti-IL6-R antibody treatment. However, transcripts encoding these cytokines were not detected among circulating immune cells. Rather, in situ analysis of lung specimens using RNAscope and immunofluorescent staining revealed that elevated IL-6 and CCL2 were dominantly produced by infected lung type II pneumocytes. Severe disease was not associated with higher viral load, deficient antibody responses, or dysfunctional T cell responses. These results refine our understanding of severe COVID-19 pathophysiology, indicating that aberrant cytokine production by infected lung epithelial cells is a major driver of immunopathology. We propose that these factors cause local immune regulation towards the benefit of the virus.
- Published
- 2021
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7. SARS-CoV-2 infection induces cross-reactive autoantibodies against angiotensin II.
- Author
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Briquez PS, Rouhani SJ, Yu J, Pyzer AR, Trujillo J, Dugan HL, Stamper CT, Changrob S, Sperling AI, Wilson PC, Gajewski TF, Hubbell JA, and Swartz MA
- Abstract
Patients infected with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) can experience life-threatening respiratory distress, blood pressure dysregulation and thrombosis. This is thought to be associated with an impaired activity of angiotensin-converting enzyme-2 (ACE-2), which is the main entry receptor of SARS-CoV-2 and which also tightly regulates blood pressure by converting the vasoconstrictive peptide angiotensin II (AngII) to a vasopressor peptide. Here, we show that a significant proportion of hospitalized COVID-19 patients developed autoantibodies against AngII, whose presence correlates with lower blood oxygenation, blood pressure dysregulation, and overall higher disease severity. Anti-AngII antibodies can develop upon specific immune reaction to the SARS-CoV-2 proteins Spike or RBD, to which they can cross-bind, suggesting some epitope mimicry between AngII and Spike/RBD. These results provide important insights on how an immune reaction against SARS-CoV-2 can impair blood pressure regulation.
- Published
- 2021
- Full Text
- View/download PDF
8. Pigeon English.
- Author
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Pyzer AR
- Subjects
- Cyprus, England, Humans, Leukemia, Myeloid, Acute psychology, Male, Narration, Culturally Competent Care, Leukemia, Myeloid, Acute therapy
- Published
- 2020
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9. When I Think About Walls.
- Author
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Pyzer AR
- Subjects
- Adolescent, Fatal Outcome, Humans, Male, Wounds, Stab surgery, Emergency Service, Hospital, Internship and Residency
- Published
- 2020
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10. Of What Remains.
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Pyzer AR
- Subjects
- Humans, Male, Aged psychology, Communication, Dementia psychology, Patients psychology, Students, Medical psychology
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- 2019
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11. Hypomethylating agent alters the immune microenvironment in acute myeloid leukaemia (AML) and enhances the immunogenicity of a dendritic cell/AML vaccine.
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Nahas MR, Stroopinsky D, Rosenblatt J, Cole L, Pyzer AR, Anastasiadou E, Sergeeva A, Ephraim A, Washington A, Orr S, McMasters M, Weinstock M, Jain S, Leaf RK, Ghiasuddin H, Rahimian M, Liegel J, Molldrem JJ, Slack F, Kufe D, and Avigan D
- Subjects
- Animals, Antineoplastic Agents, Immunological immunology, Azacitidine immunology, Azacitidine pharmacology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cell Line, Tumor, DNA Methylation drug effects, Dendritic Cells immunology, Disease Models, Animal, Down-Regulation drug effects, Down-Regulation immunology, Humans, Immunity, Cellular drug effects, Leukemia, Myeloid, Acute immunology, Mice, Inbred C57BL, Neoplasm Transplantation, Programmed Cell Death 1 Receptor metabolism, Retroviridae immunology, Virus Activation immunology, Antineoplastic Agents, Immunological pharmacology, Azacitidine analogs & derivatives, Cancer Vaccines immunology, Leukemia, Myeloid, Acute drug therapy, Tumor Microenvironment immunology
- Abstract
Acute myeloid leukaemia (AML) is a lethal haematological malignancy characterized by an immunosuppressive milieu in the tumour microenvironment (TME) that fosters disease growth and therapeutic resistance. Hypomethylating agents (HMAs) demonstrate clinical efficacy in AML patients and exert immunomodulatory activities. In the present study, we show that guadecitabine augments both antigen processing and presentation, resulting in increased AML susceptibility to T cell-mediated killing. Exposure to HMA results in the activation of the endogenous retroviral pathway with concomitant downstream amplification of critical mediators of inflammation. In an immunocompetent murine leukaemia model, guadecitabine negatively regulates inhibitory accessory cells in the TME by decreasing PD-1 (also termed PDCD1) expressing T cells and reducing AML-mediated expansion of myeloid-derived suppressor cells. Therapy with guadecitabine results in enhanced leukaemia-specific immunity, as manifested by increased CD4 and CD8 cells targeting syngeneic leukaemia cells. We have previously reported that vaccination with AML/dendritic cell fusions elicits the expansion of leukaemia-specific T cells and protects against disease relapse. In the present study, we demonstrate that vaccination in conjunction with HMA therapy results in enhanced anti-leukaemia immunity and survival. The combination of a novel personalized dendritic cell/AML fusion vaccine and an HMA has therapeutic potential, and a clinical trial investigating this combination is planned., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)
- Published
- 2019
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12. The Specter and the Goldfish.
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Pyzer AR
- Subjects
- Humans, Physician-Patient Relations, Critical Care psychology, Delirium psychology, Inpatients psychology, Physicians psychology
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- 2019
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13. Epstein-Barr virus-encoded EBNA2 alters immune checkpoint PD-L1 expression by downregulating miR-34a in B-cell lymphomas.
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Anastasiadou E, Stroopinsky D, Alimperti S, Jiao AL, Pyzer AR, Cippitelli C, Pepe G, Severa M, Rosenblatt J, Etna MP, Rieger S, Kempkes B, Coccia EM, Sui SJH, Chen CS, Uccini S, Avigan D, Faggioni A, Trivedi P, and Slack FJ
- Subjects
- B7-H1 Antigen genetics, Biomarkers, Tumor genetics, Epstein-Barr Virus Infections virology, Epstein-Barr Virus Nuclear Antigens genetics, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse metabolism, Lymphoma, Large B-Cell, Diffuse virology, Prognosis, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes virology, Tumor Cells, Cultured, Viral Proteins genetics, B7-H1 Antigen metabolism, Biomarkers, Tumor metabolism, Epstein-Barr Virus Infections complications, Epstein-Barr Virus Nuclear Antigens metabolism, Herpesvirus 4, Human immunology, Lymphoma, Large B-Cell, Diffuse immunology, MicroRNAs genetics, Viral Proteins metabolism
- Abstract
Cancer cells subvert host immune surveillance by altering immune checkpoint (IC) proteins. Some Epstein-Barr virus (EBV)-associated tumors have higher Programmed Cell Death Ligand, PD-L1 expression. However, it is not known how EBV alters ICs in the context of its preferred host, the B lymphocyte and in derived lymphomas. Here, we found that latency III-expressing Burkitt lymphoma (BL), diffuse large B-cell lymphomas (DLBCL) or their EBNA2-transfected derivatives express high PD-L1. In a DLBCL model, EBNA2 but not LMP1 is sufficient to induce PD-L1. Latency III-expressing DLBCL biopsies showed high levels of PD-L1. The PD-L1 targeting oncosuppressor microRNA miR-34a was downregulated in EBNA2-transfected lymphoma cells. We identified early B-cell factor 1 (EBF1) as a repressor of miR-34a transcription. Short hairpin RNA (shRNA)-mediated knockdown of EBF1 was sufficient to induce miR-34a transcription, which in turn reduced PD-L1. MiR-34a reconstitution in EBNA2-transfected DLBCL reduced PD-L1 expression and increased its immunogenicity in mixed lymphocyte reactions (MLR) and in three-dimensional biomimetic microfluidic chips. Given the importance of PD-L1 inhibition in immunotherapy and miR-34a dysregulation in cancers, our findings may have important implications for combinatorial immunotherapy, which include IC inhibiting antibodies and miR-34a, for EBV-associated cancers.
- Published
- 2019
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14. MUC1 inhibition leads to decrease in PD-L1 levels via upregulation of miRNAs.
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Pyzer AR, Stroopinsky D, Rosenblatt J, Anastasiadou E, Rajabi H, Washington A, Tagde A, Chu JH, Coll M, Jiao AL, Tsai LT, Tenen DE, Cole L, Palmer K, Ephraim A, Leaf RK, Nahas M, Apel A, Bar-Natan M, Jain S, McMasters M, Mendez L, Arnason J, Raby BA, Slack F, Kufe D, and Avigan D
- Subjects
- Animals, B7-H1 Antigen metabolism, Cell Line, Tumor, Humans, Immunomodulation genetics, Mice, Mucin-1 genetics, Proto-Oncogene Proteins c-jun genetics, Proto-Oncogene Proteins c-jun metabolism, Ribonuclease III genetics, Ribonuclease III metabolism, Transcriptional Activation, Up-Regulation, B7-H1 Antigen genetics, Gene Expression Regulation, Leukemic, MicroRNAs genetics, Mucin-1 metabolism
- Abstract
The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.
- Published
- 2017
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15. DCOne as an Allogeneic Cell-based Vaccine for Multiple Myeloma.
- Author
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Leaf RK, Stroopinsky D, Pyzer AR, Kruisbeek AM, van Wetering S, Washington A, Ephraim A, Cole L, Morin A, Jain S, Nahas MR, Apel A, Arnason J, Hamdan A, Rosenblatt J, and Avigan D
- Subjects
- Cancer Vaccines, Cell Differentiation, Cell Line, Tumor, Coculture Techniques, Cross-Priming, Cytotoxicity, Immunologic, Dendritic Cells transplantation, Humans, Interferon-gamma metabolism, Isoantigens immunology, Lymphocyte Activation, Multiple Myeloma immunology, Perforin metabolism, Tumor Microenvironment, Antigens, Neoplasm immunology, CD8-Positive T-Lymphocytes immunology, Dendritic Cells immunology, Extracellular Vesicles immunology, Immunotherapy, Adoptive methods, Multiple Myeloma therapy
- Abstract
Multiple myeloma (MM) is characterized by progressive immune dysregulation, loss of myeloma-specific immunity, and an immunosuppressive milieu that fosters disease growth and immune escape. Accordingly, cancer vaccines that reverse tumor-associated immune suppression represent a promising therapeutic avenue of investigation. We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted in the expansion of activated CD8 T cells expressing interferon-γ and perforin, with no significant change in the percentage of CD4 T cells producing interleukin-10. Further, coculture of patient's tumor cells with peripheral blood mononuclear cells and DCOne induced cytotoxic T-lymphocyte-mediated killing of autologous MM cells. These findings demonstrate that the allogeneic DCOne vaccine can induce T-cell activation and myeloma-specific immunity via cross presentation of antigens by native antigen-presenting cells.
- Published
- 2017
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16. Cabozantinib Eradicates Advanced Murine Prostate Cancer by Activating Antitumor Innate Immunity.
- Author
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Patnaik A, Swanson KD, Csizmadia E, Solanki A, Landon-Brace N, Gehring MP, Helenius K, Olson BM, Pyzer AR, Wang LC, Elemento O, Novak J, Thornley TB, Asara JM, Montaser L, Timmons JJ, Morgan TM, Wang Y, Levantini E, Clohessy JG, Kelly K, Pandolfi PP, Rosenblatt JM, Avigan DE, Ye H, Karp JM, Signoretti S, Balk SP, and Cantley LC
- Subjects
- Animals, Benzylamines, Cell Line, Tumor, Cell Proliferation drug effects, Chemokine CXCL12 genetics, Cyclams, HMGB1 Protein genetics, Heterocyclic Compounds administration & dosage, Humans, Immunity, Innate drug effects, Male, Mice, Neutrophils drug effects, Prostatic Neoplasms genetics, Prostatic Neoplasms immunology, Prostatic Neoplasms pathology, Protein Kinase Inhibitors administration & dosage, Tumor Microenvironment genetics, Anilides administration & dosage, Chemokine CXCL12 antagonists & inhibitors, HMGB1 Protein antagonists & inhibitors, PTEN Phosphohydrolase genetics, Prostatic Neoplasms drug therapy, Pyridines administration & dosage, Tumor Suppressor Protein p53 genetics
- Abstract
Several kinase inhibitors that target aberrant signaling pathways in tumor cells have been deployed in cancer therapy. However, their impact on the tumor immune microenvironment remains poorly understood. The tyrosine kinase inhibitor cabozantinib showed striking responses in cancer clinical trial patients across several malignancies. Here, we show that cabozantinib rapidly eradicates invasive, poorly differentiated PTEN/p53-deficient murine prostate cancer. This was associated with enhanced release of neutrophil chemotactic factors from tumor cells, including CXCL12 and HMGB1, resulting in robust infiltration of neutrophils into the tumor. Critically, cabozantinib-induced tumor clearance in mice was abolished by antibody-mediated granulocyte depletion or HMGB1 neutralization or blockade of neutrophil chemotaxis with the CXCR4 inhibitor plerixafor. Collectively, these data demonstrate that cabozantinib triggers a neutrophil-mediated anticancer innate immune response, resulting in tumor clearance. Significance: This study is the first to demonstrate that a tyrosine kinase inhibitor can activate neutrophil-mediated antitumor innate immunity, resulting in invasive cancer clearance. Cancer Discov; 7(7); 750-65. ©2017 AACR. This article is highlighted in the In This Issue feature, p. 653 ., (©2017 American Association for Cancer Research.)
- Published
- 2017
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17. MUC1-mediated induction of myeloid-derived suppressor cells in patients with acute myeloid leukemia.
- Author
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Pyzer AR, Stroopinsky D, Rajabi H, Washington A, Tagde A, Coll M, Fung J, Bryant MP, Cole L, Palmer K, Somaiya P, Karp Leaf R, Nahas M, Apel A, Jain S, McMasters M, Mendez L, Levine J, Joyce R, Arnason J, Pandolfi PP, Kufe D, Rosenblatt J, and Avigan D
- Subjects
- Animals, Cell Communication, Cell Line, Tumor, Coculture Techniques, Extracellular Vesicles pathology, Heterografts, Humans, Leukocytes, Mononuclear, Mice, MicroRNAs physiology, Proto-Oncogene Proteins c-myc biosynthesis, Cell Proliferation, Leukemia, Myeloid, Acute pathology, Mucin-1 physiology, Myeloid-Derived Suppressor Cells pathology
- Abstract
Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b
+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs., (© 2017 by The American Society of Hematology.)- Published
- 2017
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18. Bone marrow stroma protects myeloma cells from cytotoxic damage via induction of the oncoprotein MUC1.
- Author
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Bar-Natan M, Stroopinsky D, Luptakova K, Coll MD, Apel A, Rajabi H, Pyzer AR, Palmer K, Reagan MR, Nahas MR, Karp Leaf R, Jain S, Arnason J, Ghobrial IM, Anderson KC, Kufe D, Rosenblatt J, and Avigan D
- Subjects
- Antineoplastic Agents pharmacology, Cell Line, Tumor, Coculture Techniques, Cytokines metabolism, Drug Resistance, Neoplasm genetics, Gene Expression, Gene Silencing drug effects, Humans, Janus Kinase 2 metabolism, Mucin-1 genetics, Multiple Myeloma genetics, Proteasome Inhibitors pharmacology, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Bone Marrow metabolism, Bone Marrow pathology, Cell Communication, Mucin-1 biosynthesis, Multiple Myeloma metabolism, Multiple Myeloma pathology, Stromal Cells metabolism
- Abstract
Multiple myeloma (MM) is a lethal haematological malignancy that arises in the context of a tumour microenvironment that promotes resistance to apoptosis and immune escape. In the present study, we demonstrate that co-culture of MM cells with stromal cells results in increased resistance to cytotoxic and biological agents as manifested by decreased rates of cell death following exposure to alkylating agents and the proteosome inhibitor, bortezomib. To identify the mechanism of increased resistance, we examined the effect of the co-culture of MM cells with stroma cells, on expression of the MUC1 oncogene, known to confer tumour cells with resistance to apoptosis and necrosis. Co-culture of stroma with MM cells resulted in increased MUC1 expression by tumour cells. The effect of stromal cell co-culture on MUC1 expression was not dependent on cell contact and was therefore thought to be due to soluble factors secreted by the stromal cells into the microenvironment. We demonstrated that MUC1 expression was mediated by interleukin-6 and subsequent up-regulation of the JAK-STAT pathway. Interestingly, the effect of stromal cell co-culture on tumour resistance was partially reversed by silencing of MUC1 in MM cells, consistent with the potential role of MUC1 in mediating resistance to cytotoxic-based therapies., (© 2017 John Wiley & Sons Ltd.)
- Published
- 2017
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19. Myeloid-derived suppressor cells as effectors of immune suppression in cancer.
- Author
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Pyzer AR, Cole L, Rosenblatt J, and Avigan DE
- Subjects
- Animals, Cell Differentiation, Humans, Tumor Microenvironment, Immune Tolerance, Myeloid-Derived Suppressor Cells immunology, Neoplasms immunology
- Abstract
The tumor microenvironment consists of an immunosuppressive niche created by the complex interactions between cancer cells and surrounding stromal cells. A critical component of this environment are myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells arrested at different stages of differentiation and expanded in response to a variety of tumor factors. MDSCs exert diverse effects in modulating the interactions between immune effector cells and the malignant cells. An increased presence of MDSCs is associated with tumor progression, poorer outcomes, and decreased effectiveness of immunotherapeutic strategies. In this article, we will review our current understanding of the mechanisms that underlie MDSC expansion and their immune-suppressive function. Finally, we review the preclinical studies and clinical trials that have attempted to target MDSCs, in order to improve responses to cancer therapies., (© 2016 UICC.)
- Published
- 2016
- Full Text
- View/download PDF
20. Clinical trials of dendritic cell-based cancer vaccines in hematologic malignancies.
- Author
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Pyzer AR, Avigan DE, and Rosenblatt J
- Subjects
- Antigens, Neoplasm immunology, Cancer Vaccines immunology, Clinical Trials as Topic, Dendritic Cells immunology, Graft vs Host Disease immunology, Hematologic Neoplasms immunology, Humans, Transplantation, Homologous, Vaccination, Cancer Vaccines therapeutic use, Dendritic Cells transplantation, Hematologic Neoplasms therapy, Immunotherapy, Adoptive methods
- Abstract
The potential for the immune system to target hematological malignancies is demonstrated in the allogeneic transplant setting, where durable responses can be achieved. However, allogeneic transplantation is associated with significant morbidity and mortality related to graft versus host disease. Cancer immunotherapy has the capacity to direct a specific cytotoxic immune response against cancer cells, particularly residual cancer cells, in order to reduce the likelihood of disease relapse in a more targeted and tolerated manner. Ex vivo dendritic cells can be primed in various ways to present tumor associated antigen to the immune system, in the context of co-stimulatory molecules, eliciting a tumor specific cytotoxic response in patients. Several approaches to prime dendritic cells and overcome the immunosuppressive microenvironment have been evaluated in pre-clinical and early clinical trials with promising results. In this review, we summarize the clinical data evaluating dendritic cell based vaccines for the treatment of hematological malignancies.
- Published
- 2014
- Full Text
- View/download PDF
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