YOUNG INVESTIGATOR AWARDS
Adaptive is dedicated to identifying new talent to help foster growth in the immunosequencing field. Every quarter, Adaptive Biotechnologies Corporation selects one or more applicants for our Young Investigator Award to receive a $5,000 grant to use for sequencing to assist in his/her research in immunology.
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TIAGO R. MATOS, MD, MSC, PhD candidate
ACADEMIC MEDICAL CENTER, UNIVERSITY OF AMSTERDAM
Research Summary: The skin is the most commonly affected target of Graft-versus-Host-Disease (GvHD), which remains as the major cause of non-relapse mortality and morbidity of allogeneic hematopoietic stem cell transplantation. We hypothesize that expanded T cells in skin lesions of GvHD may represent the pathogenic alloreactive clones responsible for GvHD, and may be present in blood at low levels capable of being detected by next-generation high throughput sequencing of the TCR CDR3 region. A better understanding of these alloreactive T cells may allow us to track them in the blood as potential early biomarker of GvHD disease activity.
RUTH J. NAPIER, PhD
OREGON HEALTH SCIENCE UNIVERSITY
Research Summary: Although the exact causes of autoimmune arthritides are unknown, an emerging paradigm proposes that abnormal T-cell development, coupled with environmental triggers, are responsible for driving disease. I am currently investigating how host-signaling molecules, particularly those involved in innate immunity, may regulate T-cell receptor repertoire formation in arthritic mice. Defining the molecules involved in the generation and propagation of arthritogenic T cells may facilitate the development of effective therapies to treat this debilitating condition.
ISHA PRADHAN, PhD
ALLEGHENY HEALTH NETWORK
Research Summary: Thymus involution is one of the major causes of age-related decline of immune function, leading to increased susceptibility to infections, greater propensity for autoimmune diseases and cancer. Bioengineering thymus organoids de novo with isolated thymic epithelial cells (TECs) is an innovative and effective approach to rejuvenate thymic function. Our aim is to examine whether thymus organoids constructed with TECs of younger donors can effectively reverse thymus atrophy and increase the diversity of naïve T-cell repertoire in aged mice. The immunoSEQ® Technology will allow us to quantify the extent to which the transplanted thymus organoids can improve the T-cell diversity in the aged recipients. These results will help us to further optimize the T-cell generation system both in vitro and in vivo, and facilitate the translation of the technology for clinical application.
KOOROSH KORFI, PhD
Queen Mary University, London
Research Summary: Diffuse large B cell lymphoma (DLBCL) is the most aggressive and the most common type of lymphoma worldwide. The genetic landscape of DLBCL is notably enriched for abnormalities in immune surveillance mechanisms whose role in disease progression is poorly understood. In this study, I aim to investigate the clonal architecture of tumor-infiltrating T cells in paired diagnostic/relapsed DLBCL tumors to identify potential links with immune evasion mechanisms during relapse to ultimately benefit future therapeutic strategies.
AMY O’CONNEL, MD, PhD
Boston Children’s Hospital
Research Summary: As a neonatologist and pediatric immunologist, I am interested in investigating the effects of prematurity on the adaptive immune system. The project will examine the effects of prematurity on T- and B-cell repertoire diversity and development by comparing repertoires of term newborns with those of former very preterm infants who are corrected to term adjusted age. The data will help us to determine whether ex-preterm infants, who experience more infections during childhood, have persistent aberrations of their T- and B- cell repertoires following the preterm period.
KATE POROPATICH, MD
Northwestern University Medical School
Research Summary: Head and neck cancer is the fifth most common cancer in the world and up to as many as 20% of cases are caused by human-papillomavirus (HPV), a number that is continuing to grow in incidence. Compared to HPV-negative head and neck cancers, HPV-positive cases have distinctly improved clinical behavior; This improved clinical behavior could be due to higher densities of tumor infiltrating lymphocytes (TIL) in HPV-positive patients compared to HPV-negative patients. We have shown that HPV-positive cases have a unique histomorphologic pattern of peritumoral cuffing by CD3+ TIL populations that is a significant predictor of patient survival. Using the immunoSEQ® Technology, we will sequence the TCR of TILs from HPV-positive and HPV-negative patients to further elucidate immunological differences between the two, and attempt to determine whether oligoclonal T-cell populations contribute to improved survival in HPV-related head and neck carcinomas.
University of Washington
Research Summary: Systemic Lupus Erythematosus (SLE) is a complex, potentially life-threatening autoimmune disease, known to be associated with B-cell hyperactivation and the production of autoantibodies (Auto-Abs) particularly against self-nucleoproteins. The cellular origin of pathogenic cells in SLE is not well defined. Recent studies have demonstrated a link between expression levels of the ssRNA-sensing endosomal Toll-like receptor 7 (TLR7) and abnormal B-cell activation in SLE. Using immunoSEQ® Technology, we aim to examine whether specific subsets of B cells, such as newly-formed transitional B cells, from SLE patients with high expression levels of TLR7 might be enriched in poly/autoreactive specificities; and to determine which cell subsets might contribute to the production of pathogenic auto-Abs. Through this research we hope to gain a better understand the pathogenesis of SLE and provide new information on how to prevent the activation of autoreactive B cells.
Pennsylvania State University College of Medicine
Research Summary: JC polyomavirus (JCV) causes the life-threatening, demyelinating CNS disease progressive multifocal leukoencephalopathy (PML) upon pharmacological or infection induced immune suppression. Using mouse Polyomavirus (MPyV) as a model system, we recently published that the virus-specific non-lymphoid tissue resident CD8 memory T cells (Trm) have higher TCR affinity than splenic virus-specific CD8 T cells (Frost et al; J Immunol. 2015). We hypothesize that the brain resident CD8 T cells are selected for from the high affinity TCR repertoire. Using the immunoSEQ® Technology we would like to examine if the selected brain Trm population is oligoclonal and is a subset of polyclonal spleen CD8 T cells of same specificity. Results from these experiments would shed light on the mechanism of establishment of Trm populations during viral infections of CNS, in particular JCV infections.
ESTEBAN ARRIETA-BOLANOS, PhD
Institute For Experimental Cellular Therapy, Essen University Hospital
Research Summary: Non-permissive donor-recipient HLA-DPB1 mismatches are known to confer higher risks of adverse outcome after unrelated hematopoietic stem cell transplantation than permissive mismatches, but the qualitative differences in the allo-response that would explain permissiveness/non-permissiveness of HLA mismatches have not been fully characterized so far. We hypothesize that the biological basis of this differential permissiveness could relate to a greater dissimilarity of allo-peptides presented by HLA-DPB1 molecules from different T-cell epitope groups (non-permissive) compared to those in the same group (permissive), and thus our project will focus on studying the TCR-vβ diversity of CD4+ allo-responses to specific permissive and non-permissive HLA-DPB1 allele combinations in an attempt to uncover potential differences that could help us understand the immunological keys to life-threatening transplant complications, such as graft-versus-host disease and leukemia relapse.
LETIZIA AMADORI, PhD
Icahn School Of Medicine At Mount Sinai
Research Summary: Cardiovascular disease due to atherosclerosis is the leading cause of mortality and disability worldwide. T-cell infiltration has been observed at all stages of human atherosclerosis progression. Most experimental studies showing the contribution of T-cells to atherosclerosis are from mouse models. However, animal models of atherosclerosis lack of spontaneous plaque rupture—the sudden event that leads to acute cardiovascular event (i.e. stroke, acute myocardial infarction) in humans. This limitation highlights the need of studying the association between T-cell clonal expansion in atherosclerotic tissues and cardiovascular events in patients. Using the novel immunoSEQ® Technology, we will characterize T-cell receptor (TCR) clonality in human atherosclerotic tissues obtained from patients with advanced carotid atherosclerotic disease undergoing carotid endarterectomy. Results from this study will set the stage to uncover new inflammatory mechanisms involved in atherosclerosis progression towards cardiovascular events.
MATTEO DUGO, M. Sc.
Fondazione Irccs Istituto Nazionale Dei Tumori
Research Summary: Locally advanced and disseminated human melanomas are resistant to conventional therapy and characterized by poor prognosis. Inhibition of BRAF signaling with targeted therapies has recently achieved substantial survival advantage in metastatic melanoma patients with BRAFV600E- positive tumors. Despite this breakthrough, the clinical therapeutic response is extremely heterogeneous. Using immunoSEQ Technology we aim to examine the diversity of tumor-infiltrating lymphocytes (TIL) in pre-treatment lesions of patients treated with BRAF inhibitors in order to assess whether TIL clonal expansion may be a predictive biomarker of durable response.
ADHIDEB GHOSH, M. Sc.
University Zürich Hospital
Research Summary: Recently, autoantigen specific T cells were detected in psoriasis, a very common inflammatory autoimmune skin disease. Such CD8+ T-cell clones were found in the blood of 75% of psoriatic patients, but not in controls. Using immunoSEQ Technology we will investigate whether or not these clones are the same as the those found in T cells residing in psoriasis plaques and affected joints. These findings could demonstrate for the first time, a common T-cell clone driving the pathogenesis of psoriasis and psoriatic arthritis.
ASHLEY PLANT, MD
Dana Farber Cancer Institute, Children’s Hospital Boston
Research Summary: Our project will use paired pediatric brain tumor tissue and blood samples to identify the TCR repertoire present in the tumor immune infiltrate and evaluate clonal expansion. This knowledge will provide essential background information on moving forward in immunotherapies for pediatric high-grade gliomas and give insight into mechanisms of tumor immunity.
R. SWATI SHREE, MD
University Of Washington Medical Center
Research Summary: The mechanisms allowing for maternal tolerance of the semi-allogenic fetus during normal pregnancy are incompletely understood. Regulatory T-cells (T-reg cells) appear to have an important role in this process and a dysfunctional maternal T-reg response may contribute to the pregnancy disorder, preeclampsia. Using the novel immunoSEQ Technology, we plan to investigate the maternal T-reg TCR repertoire in a longitudinal cohort of uncomplicated primiparous term pregnancies and in pregnancies complicated by preeclampsia. In addition to informing future studies, we anticipate that these data will provide important insights into maternal immune adaptation with the potential to identify unique biomarkers or novel therapeutic approaches for preeclampsia.
ANDREAS AGATHANGELIDIS, PhD
Istituto Scientifico San Raffaele
Research Summary: Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries. The landmark murine model for CLL is the TCL-1 transgenic (Tg) mouse that mimics the aggressive subtype of the disease. Through the use of the novel immunoSEQ technology and Mouse TCRB Kit, we aim to obtain a deep and systematic view of the TRB repertoire in TCL-1 mice in order to address the effect of CLL-like leukemia development on the immune system. Results from this project will assist in better understanding CLL pathogenesis, how it affects the immune system and perhaps provide novel therapeutic targets.
SARAH BAXTER, MD, PhD
Seattle Children's Hospital
Research Summary: Primary Immune Deficiencies are increasingly considered part of a broader category of immune dysregulation; however, the molecular basis by which autoimmunity occurs in these diseases is not well understood. I will investigate the breadth of T- and B-cell receptors among individuals with Severe Combined Immunodeficiency possessing a unique recombinatorial protein genotype in order to better understand how global contraction of the B-cell receptor repertoire contributes to clonal expansion of auto reactive lymphocytes.
CATHERINE W. CAI
Saint Louis University School of Medicine
Research Summary: CD4+ T helper 1 (Th1) cells are known to be an advantageous immune response to infection with Trypanosoma cruzi, the intracellular parasite of Chagas disease. Recently, we discovered that CD4+ T helper 17 (Th17) cells are even more protective against T. cruzi infection than Th1 cells. Using immunoSEQ Technology, we will investigate the differential effects of priming by Th1 versus Th17 cell help on CD8+ T cell receptor repertoires in the context of infection.
GEORG J. FURTMÜLLER, MD
Johns Hopkins University, School of Medicine
Research Summary: Using immunoSEQ TCRB receptor sequencing, we aim to identify the frequency and fait of alloantigen-specific T cell clones in a murine model of vascularized composite allotransplantation after the application of a novel peri-transplant cyclophosphamide-based treatment protocol for tolerance induction.
THET SU WIN, MD, PHD
Brigham and Women's Hospital
Research Summary: Unlike solid organ transplants, vascularized composite allotransplants (VCAs), such as face transplants, have a unique immunological characteristic – the presence of skin, which contains ~1 million T cells/cm2. Although the effector role of T cells in acute rejection is well established, the contribution of donor versus recipient T cells in rejection of VCAs is unexamined. This project, using tissue samples from the largest cohort of face transplant patients at a single center in the world, will investigate the turnover of donor T cells within facial allografts following transplant, and if the pathogenic T cell clones implicated in acute rejection are derived from donor or recipient.
FRANSENIO CLARK, BS
University of Massachusetts Medical School
Research Summary: CD8 T cell memory specific to both influenza A virus (IAV) and Epstein Barr Virus (EBV) is modulated with increasing age of individuals. I will be studying the role of the T- cell receptor repertoire in the generation of antigen specific and cross reactive cells.
LAURA COOK, PhD
University of British Columbia, Child and Family Research Institute
Research Summary: Clostridium difficile (C. difficile) is a toxin-secreting bacterial species that is the leading cause of hospital-acquired infectious diarrhea, and although antibiotic treatments are available, approximately one third of patients suffer relapsing infections. We are currently unable to predict relapse, meaning physicians cannot target at-risk patients to receive newer treatments, which have been proven to reduce relapse rates. My project centers on characterizing, for the first time, the population of CD4+ T cells that recognize the pathogenic toxin B (TcdB) secreted by C. difficile. I will be conducting T-cell receptor repertoire analyses on these cells from patient’s current C. difficile infections that do and do not experience relapse. My central hypothesis is that a skewed TCR repertoire within toxin-specific CD4+ T cells may be a risk factor for relapsing infection.
German Cancer Consortium
Research Summary: Using immunoSEQ T-cell receptor sequencing, we aim to identify patterns in the breadth and maturation of anti-tumor immune responses to melanoma. Ultimately we will test whether the T-cell receptor clonality, mutational load and the composition of the immune cell infiltrate are correlated with clinical course in melanoma patients.
University of Texas Health Science Center at San Antonio
Research Summary: Manipulation of the immune system to defeat cancer is a promising new strategy; however, so far only a subset of patients experience clinical benefit. My project will examine T cell receptor diversity in mice that exhibit tumor regression in response to depletion of deleterious regulatory T cells versus mice that do not exhibit tumor regression after treatment. Thus, we define immune characteristics of treatment responders and nonresponders and help guide the clinical implementation of regulatory T cell depletion agents for cancer patients.
University of Texas MD Anderson Cancer Center
Research Summary: Despite recent advances in the treatment of metastatic melanoma through targeted and immunotherapy, the majority of patients do not achieve a durable response. In recent years, tumor heterogeneity has been suggested to be a contributor to resistance to therapy in metastatic melanoma. Considering the high reliance of current cancer therapies on an effective immune response, we’ve begun characterizing the molecular and immune heterogeneity in synchronous melanoma metastases with the goal of identifying actionable strategies to improve on the success of current therapeutic regimens.
Research Summary: Mechanisms of human naive T cell maintenance in the context of antigen encounter and decreasing thymic output over life are unknown chiefly because studies on human T cell development have been limited to analysis of peripheral blood and the intrinsic variations seen between humans and mice. We will use TCR sequencing to study the dynamics of naive T cell maintenance over decades of life directly in human lymphoid and mucosal tissue sites to better understand their longevity and residence.
Centre de Recherche du Chum, Institut duCcancer de Montréal
Research Summary: The goal of our study is to identify and characterize the functionality of mutation-reactive T cells in patients with metastatic colorectal cancer in order to ultimately develop novel, personalized and effective immunotherapies for this common malignancy.
AMY MORAN, PhD
Earle a Chiles Cancer Research Institute
Research Summary: The generation of T cell specific immunological responses to tumor-associated antigens is enhanced with immunotherapy agents that block T cell inhibitory molecules or promote co-stimulation of antigen specific T cells. We are interested in how these single and/or combination immunotherapy agents modify the T cell repertoire to tumor associated antigens and how similar or diverse this repertoire is between individual hosts.
JILLIAN RICHMOND, PhD
University of Massachusetts Medical School
Research Summary: Vitiligo is an autoimmune skin disease caused by CD8+ T cells that target melanocytes for destruction, resulting in patchy depigmentation that is disfiguring and distressing to patients. It affects approximately 1% of the population worldwide, yet there are currently no FDA approved treatments. Depigmentation often recurs at the same location after therapy is stopped, though the mechanism for this is unknown. We hypothesize that utoreactive resident memory T cells (Trm) persist in the skin and cause this disease reactivation after cessation of treatment. Preliminary data from our lab indicate that cells with a Trm phenotype are present in vitiligo skin, however we do not know their antigen specificities. Therefore, we will use the immunoSEQ technology to perform TCR V-beta sequencing to identify clones present in lesional vitiligo skin that differ from non-lesional skin. Once we have this information, we can begin to track specific clones over time to determine if treatments are depleting or inhibiting them. We expect that targeting Trm will prove to be a more durable and robust treatment approach for vitiligo, thereby changing the lives of millions of patients who are devastated by this disease.
Beth Isreal Deaconess Medical Center
Research Summary: Public T cell responses to a specific epitope are the result of shared T cell receptor (TCR) sequences among multiple individuals. Public TCR were previously regarded as an unusual phenomenon, owing to the apparent low probability of the same TCR being observed in multiple individuals responding to the same epitope. We will use ImmunoSEQ in order to screen for human leukocyte antigen – restricted public TCR sequences in response to polyoma virus JC, which is the etiologic agent of progressive multifocal leukoencephalopathy. Our goal is to understand the significance of public TCR against viruses and translate our findings into clinically useful applications.
Research Summary: Achievement of donor-specific immunologic tolerance is key to eliminating the need for chronic immuno-suppression in transplant recipients. Recent advances in transplant tolerance research have indicated that the use of ex vivo expanded regulatory T cells (Tregs) may achieve this elusive goal. Their increased presence have been associated with immunologic tolerance to organ transplants and with improved outcome in allograft rejection. Under physiological conditions these Tregs, however, are of low abundance. Therefore, ex vivo expansion is required to harness their therapeutic potential. By T cell receptor repertoire screening we will be able to more reliably monitor changes in cellular make up during the Treg culture, to track cell plasticity and help identify inflammatory cell subsets that would otherwise be deleterious to organ transplants. Key to the success of this project is identification of a TCR repertoire as a Treg signature that defines effective Treg population.
University Pierre And Marie Curie, Inserm U974
Research Summary: Therapeutic efficacy following in vivo gene transfer has been demonstrated in several clinical trials. However, the scope of this approach in humans appears to be limited by T cell responses directed against the viral vector used as gene delivery vehicle. We plan to use to the immunoSEQ technology to follow the TCR repertoire in humans undergoing gene transfer and track T cell clonality in different tissues at baseline and following vector administration.
Haartman Institute, University Of Helsinki
Research Summary: The enormous diversity of our immune system is created in thymus by genetic rearrangement of TCR alpha and beta chains. We would like to perform a deep sequencing analysis of human thymic TCR beta repertoire. The aim is to estimate what is the number and diversity of TCR beta repertoire in human thymus.
YVES T. FALANGA, PhD
University Of Massachusetts Medical School
Research Summary: Approximately 90-95% of adult individuals have latent Epstein-Barr virus (EBV) infection. In immune-sufficient patients, numerous factors contribute to the containment of EBV, such as the ability of EBV-specific CD8+ T cells to appropriately respond upon cognate antigen stimulation. Generally, infected individuals remain seropositive for EBV throughout their entire life. Although EBV reactivation from latency is not frequent and often causes no harm, it is associated with lymphoproliferative diseases like Burkitt’s lymphoma in rare cases. Recent studies demonstrate increased incidence in Burkitt’s lymphoma in EBV-infected patients residing in malaria-endemic areas, suggesting an association between malaria infection, EBV reactivation and the development of Burkitt’s lymphoma. Using the ImmunoSEQ technology platform, we aim to study the diversity of the T cell repertoire in single individuals over time using malaria infection as an ecological variable. This will allow us to assess not only patient-specific variations of the T cell repertoire over time but also inter-patient variations. Furthermore, we will study longitudinal variations of the T cell repertoire in Burkitt’s lymphoma patients before and after chemotherapy treatment.
The Rockefeller University
Research Summary: Diphencyprone (DPCP) is a hapten that causes delayed-type hypersensitivity reactions upon conjugation with endogenous proteins and is widely used to test immune status, yet the antigen(s) responsible are unknown. We plan to study the TCR repertoire of human skin samples at various time points following the inflammation induced by DPCP, with the hope of better understanding the clonality of these reactions as well as how long the T cells persist.
Washington University in St. Louis
Research Summary: Generation of the pre-selection T cell repertoire is a multifactorial process, driven by genetic, epigenetic and structural components. It is essential to develop a deeper understanding of the mechanisms that sculpt V segment selection during VDJ recombination. We have developed mouse models which separate the phenomenon of long range interaction from the epigenetic landscape. Using immunoSEQ, we plan to dissect how changes in chromosome looping alter the fine-tuning of the T cell receptor beta repertoire.
IOANNIS POLITIKOS, MD
Beth Israel Deaconess Medical Center
Research Summary: Patients undergoing umbilical cord blood transplantation (UCBT) have increased risk for reactivation of human herpesvirus 6 (HHV-6), which is the leading cause of central nervous system complications after UCBT. In order to understand the immunologic mechanisms responsible for HHV-6 reactivation, we will use the immunoSEQ technology to characterize and monitor the TCR repertoire in response to HHV6. First, we will use T cells from patients with high levels of HHV-6 viremia for in vitro stimulation with immunogenic HHV-6-specific peptides and we will identify TCR dominant clones by deep sequencing of the Vb TCR locus. Subsequently, we will perform deep sequencing analysis in the T cells of UCBT recipients with and without HHV-6 viremia, in order to investigate the existence and dominance of HHV6-specific clones in vivo. These studies will determine the quantitative and qualitative profile of the HHV-6-specific responses overtime. Furthermore, by correlation with clinical outcomes, our studies may enable the identification of UCBT recipients at high risk for uncontrolled reactivation of HHV-6, which represents the most serious cause of post-transplant encephalitis.
WADE IAMS, MD
Vanderbilt University Medical Center
Research Summary: Small cell lung cancer (SCLC) is an aggressive form of lung cancer with a poor prognosis. Since treatments and outcomes for patients with SCLC have not significantly changed over the past 30 years, there is an urgent need to define novel therapeutic strategies. Recently, immune checkpoint inhibitors have successfully been used to treat patients with SCLC. However, there are limited data supporting biomarkers of response to these agents. We hypothesize that characterization of the immune repertoire of T cells infiltrating tumors in patients with SCLC will provide insight into an underlying immunologic signature that predicts response to immune checkpoint inhibition.
University Of Washington School Of Medicine
Research Summary: Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer caused by Merkel Cell Polyomavirus (MCPyV). Over half of MCC patients mount an adaptive immune response to the MCPyV T-Antigen, and patient survival is positively correlated with tumor infiltration by CD8+ T cells. We propose to tetramer sort HLA*A02:01-restricted T cells recognizing one commonly immunogenic MCPyV epitope from PBMC of MCC patients and use the immunoSEQ platform to determine the TCR alpha and beta repertoire of these CD8+ cells. We hope to detect any public TCRs among this cohort, as well as possible differences in repertoire among patients with different disease courses.
Research Summary: Using TCRbeta sequencing to understand how the anti-tumor immune response infiltrating meningiomas impacts tumor progression and predicts malignancy.
DAVID B. PAGE, PhD
Memorial Sloan-Kettering Cancer Center
Research Summary: In locally advanced breast cancer, lymphocytic tumor infiltration correlates with long-term survival following neoadjuvant chemotherapy. We will utilize the platform to test the hypothesis that chemotherapy serves to ‘auto-vaccinate’ against tumor antigens, generating a clonal T-cell response that might be protective against recurrence.
XIAOTI GUO, PhD
North Shore-Lij Health System
Research Summary: Natural antibodies bind and eliminate infectious microbes, but also can bind self components and help dispose of cellular debris, thereby avoid activation of the immune system and initiation of autoimmune disease, including lupus. We will study human anti-phosphorylcholine (PC) autoantibody that we propose works to prevent lupus, to learn what B lymphocytes produce this antibody, how the antibody binds PC, whether the antibody is different when it comes from healthy individuals vs patients with lupus, and whether the antibody protects animals predisposed to develop lupus. We will perform next-generation sequencing with the immunoSEQ platform to examine the repertoire and structure of anti-PC antibodies. The deep sequencing data will tell us whether B1 cell-derived anti-PC Ab is distinct in terms of VDJ usage, CDRH3 properties, N-addition and VH mutation when compared with other B cell subsets; and whether B cells of autoimmune patients produce qualitatively and quantitatively distinct anti-PC Abs.
KRITHIKA KODUMUDI, PhD
H. Lee Moffitt Cancer Center
Research Summary: Adoptive transfer of tumor infiltrating lymphocytes (TIL) has emerged as a promising approach to induce effective anti-tumor immunity and tumor regression. Although T cells are able to infiltrate tumors, studies have shown that TIL are inactivated in vivo due to various suppressive factors in the local tumor microenvironment, including regulatory T cells, myeloid derived suppressor cells, and co-inhibitory receptors such as CTLA-4 and PD-1. We hypothesize that blockade of the PD-1/ PD-L1 pathway will lead to increased T cell diversity within tumors. Our aim is to characterize the immune repertoire of T cells (TCRbeta) infiltrating tumors. Using immunoSEQ technology, characterization of TIL will reveal the clonal composition of T cell populations and provide insight into the clonality and heterogeneity of the TIL in solid tumors after PD-L1 blockade.
VINAY S MAHAJAN, MD, PhD
Center For Cancer Research, Massachusetts General Hospital
Research Summary: IgG4-related disease is a chronic immune-mediated condition characterized by extensive tissue fibrosis and is treatable by rituximab with an excellent clinical response in nearly all patients. However, the disease relapses after 6-12 months in a subset of individuals and we have found that relapse is heralded by the reemergence of specific disease-associated T and B cell populations. We intend to use the immunoSEQ platform for quantitative repertoire analysis of these lymphocyte subsets to assess the mechanism of post-rituximab disease relapse in these patients.
Research Summary: Lung cancer is the leading cause of cancer-related death worldwide. To gain insights into how the immune system plays a role in lung tumorigenesis, we propose to use immunoSEQ technology to study the T cell repertoire in human lung cancer specimens.
MATTHEW RAUSCH, PhD
University Of Arizona College Of Medicine
Research Summary: The processing and presentation of peptide antigens by professional antigen presenting cells is a critical first step in the initiation of T cell-mediated immune responses. Studies in mice have revealed that altering the cellular antigen processing machinery of antigen presenting cells can significantly change the self peptide repertoire presented under steady state conditions. However, the impact of this altered antigen presentation on the T cell repertoire has not been investigated. I will use the immunoSEQ technology to analyze how altering the antigen processing machinery of mouse antigen presenting cells impacts the T cell repertoire. The results of this project are anticipated to provide us with new insights into how antigen processing and presentation affects T cell responses with implications for the treatment of autoimmunity and cancer.
LAUREN HENDERSON, PhD
Boston Children’s Hospital
Research Summary: Juvenile Idiopathic Arthritis (JIA) is the most common rheumatologic disorder affecting children yet the cause of this disease is unknown. Past studies have demonstrated the importance of T lymphocytes in JIA. By characterizing the T cell repertoire in the synovial fluid and peripheral blood of patients with JIA, I hope to further elucidate the pathogenesis of this disease.
DAVID BERNAL, PhD
Universidad Nacional De Colombia
Research Summary: In our laboratory we are working on the immunogenicity of tumors in breast cancer patients. With immunoSEQ we will sequence CD8 specific tumor antigen TCR from those patients and total CD8 TCR before and after chemotherapy to evaluate if the repertoire frequency of specific T cells is altered by cancer treatment and correlate these results with their clinical response.
KIRSTIN HEUTINCK, PhD
Academic Medical Center Amsterdam
Research Summary: In kidney transplant recipients, the presence of virus-specific T cells with cross-reactivity to allogeneic-HLA molecules of donor origin, may negatively influence transplant outcome. To characterize cross-reactive T cell responses in transplant recipients, I will the immunoSEQ technology to analyze the clonality of the response and to follow cross-reactive T cell clones in time.
JAMIE LYNN HARDEN, PhD
The Rockefeller University
Research Summary: Psoriasis is a chronic, debilitating inflammatory skin disease characterized by red, scaly plaques. Although the role of T cells in this disease has been well established, the antigen specificity of the pathogenic T-cells in psoriasis is largely unknown. Additionally, gamma-delta T-cells have been gaining interest as a cellular contributor to psoriasis. In this pilot study, both the gamma and the beta human T-cell immunoSEQ platforms will be utilized to compare the T-cell repertoire in normal and psoriatic skin. A more detailed understanding of the T-cell populations in psoriasis is a critical next step to elucidating the etiology of this disease, as well as possible new therapeutic targets.
ALAN WATSON, PhD
University Of Pittsburgh
Research Summary: T cell responses elicited by the live-attenuated Yellow Fever Virus (YFV) Vaccine play a role in protecting the host against infection with wild-type (wt)YFV in our mouse model; however, non-vaccinated mice succumb to disease following wtYFV infection despite eliciting surprisingly high numbers of polyfunctional T cells. I will use the immunoSEQ system to compare the clonotypic diversity of T cells elicited following vaccination or infection with wtYFV and ask whether differences in T cell repertoire may explain immune control of the YFV vaccine and immune evasion by wtYFV.
SVEN MALCHOW, PhD
University of Chicago, Department Of Pathology
Research Summary: In a recent study, we demonstrated that the thymic development of some naturally occurring Foxp3+ regulatory T cells (Tregs) is dependent on the transcriptional regulator Aire (autoimmune-regulator). Aire expression in the thymus drives the ectopic expression of peripheral tissue self antigens, and Aire-deficiency in mice and humans results in multi-organ autoimmunity. The relative contribution of Aire-dependent Tregs to the peripheral Treg pool is unknown. I will use the immunoSEQ technology to elucidate the prevalence of Aire-dependent Tregs within the peripheral repertoire by determining the extent of TCR β chain repertoire overlap between CD4+Foxp3neg and CD4+Foxp3+ T cell populations derived from wild-type and Aire-deficient mice. The results of this study are anticipated to provide new insights into the antigen specificities and development of Tregs, with implications for the treatment of autoimmunity and cancer.
King’s College London
Research Summary: We would like to perform analysis of TCR beta repertoire diversity of CD4+ T cell found in non-reactive lymph nodes from healthy individuals. These studies would broaden our understanding of the dynamics of T cell circulation and retention in lymph nodes in normal health. In addition, they would serve as reference point for our studies looking into the changes in the TCR beta diversity in chronic lymphocytic leukemia and will hopefully help other researchers to interpret the results of their studies on TCR diversity in other disease-involved lymph nodes.
Centro Ricerca Tettamanti University of Milan Bicocca
Research Summary: Acute lymphoblastic leukemia with the Mixed-Lineage Leukemia gene rearrangement occurring within the first year of age (MLL+ Infant ALL) is a very aggressive disease, associated to an overall dismal prognosis, in which the MLL gene rearrangement is the pre-natal and powerful genetic event driving and hastening the leukemia initiation.
By clonal studies in relapsed patients, and serial xeno-trasplantation assays into immune deficient NOD/SCID mice, we have uncovered an exceptional clonal diversity and competition/selection of multiple co-existing leukemic clones (as for example we have observed that dominant clones at disease presentation might persist or extinguish at relapse; whilst ‘new’ clones, which were indeed minor component of the leukemic bulk but quiescent at diagnosis, might reactivate and take over at relapse).
In the proposed study we will perform next-generation profiling of Ig/TCR gene rearrangements in order to i. further dissect the clonal composition of MLL+ leukemia and ii. follow the dynamics of competition/selection of multiple pre- existing leukemia-initiating clones during disease progression; both in paired diagnosis/relapse samples from MLL+ infant ALL patients, as well as in xenograft leukemia samples from serially transplanted mice.
JENNIFER SIMS, PhD
Columbia University Medical Center
Research Summary: Glioblastoma multiforme (GBM) remains the most aggressive and prognostically devastating primary brain tumor, unusually persistent in the face of surgical, chemotherapeutic, radiological intervention. We are studying the links between glioma progression (and suppression) and perturbation of the T cell population within the tumor and the periphery with both human patient samples and our murine model.
GAURAV GAIHA, PhD
Ragon Institute of MGH, MIT and Harvard
Research Summary: Given recent findings implicating the role of CD8+ T cell receptor clonotypes in HIV control, we propose using the immunoSEQ platform to profile the entire TCR beta repertoire of HIV-specific CD8+ T cells from patients with known periods of controlled and progressive infection. This unique intra-patient comparative approach would provide a first in-kind perspective on the global changes in HIV-specific TCR repertoires that account for these divergent clinical presentations, ultimately guiding further development and monitoring of efficacious T cell based vaccines.
ERIC ALLENSPACH, PhD
Seattle Children’s Hospital
Research Summary: My project proposal is to compare the naïve B cell IgH repertoire of normal human control samples with patients with human primary immunodeficiency syndromes. Many patients have autoimmunity symptoms that may be explained by a shift in the peripheral B cell repertoire.
TAIZO NAKANO, MD
Children’s Hospital Colorado
Research Summary: Neuroblastoma, the most common extracranial solid tumor in infants and young children, accounts for 15% of childhood cancer mortality. We hypothesize that T cells actively undergo clonal expansion in response to neuroblastoma and that overrepresented T cell receptor repertoire sequences will act as diagnostic and/or prognostic tools that will influence treatment decisions and lead to novel antigen discovery. Variations in the diversity of the anti-tumor immune repertoire amongst patients with stage IV neuroblastoma, between patients of low stage and high stage disease, and after the administration of induction chemotherapy will greatly expand our current understanding of neuroblastoma immunology.
University of Birmingham, UK
Research Summary: Primary sclerosing cholangitis (PSC) is a chronic liver disease, characterized by progressive inflammation, fibrosis and destruction of the bile ducts. Studies suggest that T cells play a pivotal role in the progression of PSC disease. In this project, we propose to isolate T cells from human PSC liver tissue and matched peripheral blood and using the immunoSEQ technology to profile the human T cell receptor beta, in order to investigate the presence of specific TCRs in PSC patients that will help us understand what antigens might be able to interact with the variable regions and thus identify what causes the activation of T cells in human PSC liver.
KYLE K. PAYNE
Virginia Commonwealth University – Massey Cancer Center
Research Summary: Through the use of ultrahigh-throughput sequence analysis, this project proposes to determine whether the T cells of patients with breast cancer exhibit a unique molecular signature in VDJ gene recombination of the TcR Vβ following an ex vivo T cell expansion and re-programming protocol developed by our group. The existence of distinct TcR clonotypes in re-programmed T cells would provide rationale for future immunomonitoring of TcR Vβ recombination in breast cancer patients in order to predict objective responses following initial therapy.
Research Summary: Obesity is a chronic inflammatory condition characterized by activation and infiltration of T cells into adipose tissues, which is an integral step in the development of associated metabolic syndromes such as diabetes. The goal of this project is to analyze the variable region of T cells in adipose tissue from obese patients with type-2 diabetes using a high-throughput sequencing method in order to better understand the role of T cells in the pathophysiology of this disease.
Baylor College of Medicine
Research Summary: We have an ongoing clinical trial where we infuse virus-specific T cells derived from cord blood into cord blood transplant recipients. Using TCR sequencing, we are trying to determine whether the T cells that we give to the patients persist in vivo and correlate with protection or resolution of viral infections.
For Research Use Only. Not for use in diagnostic procedures.