Precision Immunology Institute at Icahn School of Medicine at Mount Sinai (PrIISM)

Cancer Immunology

The development of checkpoint inhibitors and adoptive T cell therapies has led to remarkable recent achievements in cancer treatment with the induction of dramatic and durable responses in cancers traditionally thought to have poor outcomes. These accomplishments are heralding a new chapter in cancer that has changed treatment platforms and paradigms. Yet the success of these therapies, although significant, is still limited to subsets of patients.

PrIISM joined effort with the Tisch Cancer institute (our NCI designated Cancer center) to build a state of the art Cancer Immunology (CI) program that assembled basic and clinical immunologists with the common goal to develop scientifically-based strategies that will expand the current platforms and increase the potency of immunomodulatory approaches against cancer. CI members focus on ways to improve immunogenicity locally within the tumor microenvironment, increase tumor antigen presentation and reduce tumor-associated immunosuppression. These strategies have the potential to dramatically augment T cell-mediated anti-tumor immunity and are being tested by our group either alone or in combination with checkpoint inhibitor therapy.

Investigators with a major focus in cancer immunology include:

Nina Bhardwaj, MD, PhD is an immunologist who has made seminal contributions to human dendritic cell biology, specifically with respect to their isolation, biology, antigen presenting function, and use as vaccine adjuvants in humans. She is the Director of Immunotherapy at the Icahn School of Medicine at Mount Sinai (ISMMS) and holds the Ward Coleman Chair in Cancer Research. Dr. Bhardwaj brings expertise in human immunology and a variety of immune therapies, having developed Toll Like Receptor (TLR) agonist- and dendritic cell-based vaccines for the treatment of both cancer and infection in several Investigator-Initiated studies. Dr. Bhardwaj is an elected member of the American Society of Clinical Investigation and the American Association of Physicians, a recipient of the Doris Duke Distinguished Scientist Award and was named one of the Scientific American Magazine’s Top 50 Researchers, receiving the Award for Medical Research in 2004. She received the Fred W. Alt Award for new discoveries in Immunology in 2015 from The Cancer Research Institute. Dr. Bhardwaj is a senior editor of the AACR Cancer Immunology Research journal, senior editor for Frontiers in Immunology and consulting editor for the Journal of Clinical Investigation. She has also served on NIH Study Sections and multiple advisory councils. Dr. Bhardwaj was formerly chair of the Cancer Immunology Steering Committee of the AACR. Dr. Bhardwaj has also successfully acquired multiple federal and foundation grants and has authored over 200 publications.

Area(s) of Focus:
Cancer Immunology 

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Dr Brody is the Director of the The Lymphoma Immunotherapy Program at the Mount Sinai School of Medicine. The Program and the Brody Lab focus on basic and applied tumor immunology (particularly in lymphoma, melanoma, and ovarian adenocarcinoma). Other areas of interest include: bioinformatic-based collaborations tracking T-cell responses using high-throughput sequencing of the entire TCRbV repertoire and studies of small-molecule inhibitors of lymphocyte signal transduction, e.g. PI3K, mTOR, btk. The lab has the rare opportunity to both perform correlative studies on primary patient tumor samples from early phase clinical trials and to continually develop advancements in those trials based on what is learned. The core mission is the translation of basic science in tumor immunology into novel clinical trials and development of correlative science associated with those trials to gain a greater understanding of mechanistic-clinical correlates.

Area(s) of Focus:
Cancer Immunology

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Brian Brown, PhD is an Associate Professor in the Department of Genetics and Genomic Sciences and the Associate Director of the Precision Immunology Institute (PrIISM) at Mount Sinai. His research is aimed at identifying factors that control immunity and tolerance, and utilizing this information for developing therapeutic strategies that can direct immune responses. He has helped identify several factors involved in the regulation of dendritic cell development and function, including a novel microRNA and receptor tyrosine kinase axis. His lab also has a strong emphasis in the generation of new technologies for experimental and therapeutic applications. Dr. Brown developed a novel gene targeting technology, which is widely used for enhancing vector and virus-based drugs in applications ranging from the treatment of genetic diseases to cancer therapy to viral vaccines. His lab also developed the first genome-wide technology to measure miRNA activity at single cell resolution, and aided in the invention of an improved method for deep sequencing small RNAs. Recently, they generated a new technology, called the Jedi, to probe the interactions between T cells and tissues at a granular level, and to learn how cancer cells evade immunity. 

Area(s) of Focus:
Cancer Immunology 

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Steven Burakoff, MD is the Dean for Cancer Innovation and Lillian and Henry M. Stratton Professor of Cancer Medicine at the Icahn School of Medicine at Mount Sinai. Dr. Burakoff is an immunologist who had made seminal contributions to the understanding of T cell biology, focusing on mechanisms of activation, signal transduction pathways and negative regulatory mechanisms that control immune responses. Currently, Dr. Burakoff is focusing his research interest on understanding the role of hematopoietic progenitor kinase 1 (HPK1) – a hematopoietic cell-restricted serine/threonine kinase that functions as a negative regulator of TCR-induced T cell activation. Dr. Burakoff’s laboratory is working closely with Pfizer Pharmaceutical to develop small molecule inhibitors to block HPK1 catalytic activity. It is the goal of this research to develop the first oral available small molecule immuno-oncology drug capable of stimulating dormant or tolerized immune cells so they can robustly engage and eliminate cancer cells. Dr. Burakoff has authored more than 400 academic publications. He is Director Emeritus of the Tisch Cancer Institute and is the recipient of numerous awards including the American Association of Immunologist’s Life Time Achievement Award.

Area(s) of Focus:
Cancer Immunology

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Hearn Jay Cho MD, PhD is an Associate Professor of Medicine and an Attending Physician with the Multiple Myeloma Service at the Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai. Dr. Cho’s laboratory is investigating novel therapies for multiple myeloma in two areas. First, they are investigating combination immunologic therapies including tumor vaccines, checkpoint inhibitors, and targeting antibodies in clinical trials and associated laboratory research, using genomic and immunologic analysis to understand the mechanisms of these agents and develop rational combinations. This program has a special focus on immunologic therapy in the setting of autologous stem cell transplantation. Second, Dr. Cho’s laboratory discovered that two of the type I Melanoma Antigen Genes (MAGE), MAGE-A3 and MAGE-C1, are commonly expressed in multiple myeloma and are correlated with progression of disease and proliferation. They demonstrated that MAGE play critical roles in conferring resistance to chemotherapy and inhibition of apoptosis in myeloma cells through regulation of Bcl-2 family proteins. Dr. Cho’s group is conducting biochemical and structural biological studies to identify novel pharmacologic strategies for inhibition of type I MAGE anti-apoptotic activity in myeloma. The ultimate goal is combination therapy with targeted agents, vaccines, and other immunotherapeutic strategies in pursuit of curative therapy for multiple myeloma. 

Area(s) of Focus:
Cancer Immunology

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Jose C. Clemente, PhD is an Assistant Professor of Genetics & Genomic Sciences and Immunology and member of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. Dr. Clemente's laboratory studies the human microbiome and its effect on human diseases. His laboratory has made critical findings in characterizing the microbiome of human populations and in understanding how deviations from microbial homeostasis is associated with immune disorders. Dr. Clemente's laboratory has also pioneered studies on how to modify the microbiome, both in early life and in adulthood, in order to restore homeostasis. He is an Associate Editor of Microbiome and mBio, and has published over 70 articles in high profile journals.

Area(s) of Focus:
Allergy
Inflammatory Bowel Disease 
Microbiome and Host Pathogen Interaction 

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David Dominguez-Sola, MD, PhD is an Assistant Professor of Oncological Sciences and a faculty member of the Tisch Cancer Institute (TCI) at the Icahn School of Medicine at Mount Sinai. His laboratory studies the biology of germinal center B cells as it relates to the pathogenesis of B cell non-Hodgkin lymphomas. Dr. Dominguez-Sola contributed to seminal discoveries on the role of the proto-oncogene c-MYC during normal B cell responses and B cell lymphomagenesis. These include the identification of a novel role for MYC in the control of DNA replication and its requirement for the initiation and maintenance of germinal center responses and antibody affinity maturation, findings that have important conceptual implications for our understanding of the role of this proto-oncogene in B cell lymphomas. Recently, his group discovered an essential role for FOXO1 in establishing architectural and functional polarity in germinal centers. These studies have been featured in diverse high impact journals, and are a source of active collaborations with leading groups at several institutions (Columbia U, Rockefeller U). Dr. Dominguez-Sola is a NIH K99/R00 awardee.

Area(s) of Focus:
Cancer Immunology 

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Jeremiah Faith, PhD received his PhD in Bioinformatics and Systems Biology from Boston University. He did his postdoctoral training in the laboratory of Jeffrey Gordon at Washington University in St. Louis Medical School with a focus on the structure and function of the gut microbiome in healthy individuals. He is currently an Assistant Professor in the Immunology Institute and the Institute for Genomics and Multiscale Biology in the Icahn School of Medicine at Mount Sinai in New York. He is also director of the Icahn School of Medicine at Mount Sinai’s Gnotobiotic Facility and co-director of the Immunology Training Area. Dr. Faith’s lab studies the interactions between diet, gut microbes, and host physiology with an emphasis on Inflammatory Bowel Disease.

Ongoing research in the lab includes:

  • Quantifying the influence of diet and the gut microbiota on host health and disease.
  • Understanding the impact of interpersonal variation in gut microbiome composition on host phenotypic variation.
  • Optimizing the engraftment of live bacterial therapeutics.
  • Tracking the stability and transmission of the human gut microbiota. 

Area(s) of Focus:
Inflammatory Bowel Disease
Cancer Immunology
Microbiome and Host Pathogen Interaction

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James L. M. Ferrara, MD, DSc is the Ward-Coleman Professor of Cancer medicine and Director of the Center for Translational Research in Hematologic Malignancies in the Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai in New York City. His research focuses on the immunology of bone marrow transplantation (BMT), particularly its major complication graft-versus-host-disease (GVHD). His team has identified and validated the first clinically useful biomarkers for acute GVHD and illuminated unexpected interactions between the innate and adaptive immune systems, leading to conceptual breakthroughs and the discovery of novel therapeutic targets.

 

 

Area(s) of Focus:
Transplant
Cancer Immunology

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Dr. Sacha Gnjatic, PhD is an Associate Professor and the Associate Director of the Human Immune Monitoring Center at the Icahn School of Medicine at Mount Sinai

Dr. Gnjatic’s lab focuses on human immune responses to cancer in an antigen-specific manner, in the periphery and at the tumor site, to define new targets for the development of cancer immunotherapies, how they work and why they may fail. Dr. Gnjatic’s work on tumor antigens has established the immunological basis for testing cancer vaccines in over 40 clinical trials, opening a new field of cancer immunology based on clinical discovery, with the goal to achieve protective integrated immune responses in the fight against cancer. Dr. Gnjatic’s laboratory has pioneered novel high-dimensional techniques and served as reference for harmonized immunomonitoring of humoral, cellular, and tissue-based immune correlates, which has led to the adoption of new standards by other labs.

Area(s) of Focus:
Cancer Immunology
Inflammatory Bowel Disease 

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Amir Horowitz, PhD is an Assistant Professor of Oncological Sciences at the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. Dr. Horowitz’s laboratory studies human NK cells and the genetic and environmental determinants underlying their education and ability to respond in dynamic environments. Dr. Horowitz’s work is contributing to developing an understanding of adaptive NK cells and their roles in microbial infections, cancers, autoimmunity as well as following vaccination and hematopoietic cell transplantation (HCT). He was the first to demonstrate adaptive roles for NK cells in vaccine settings as a strategy to potentiate T cell memory and also pioneered the first studies of human NK cells by CyTOF. His research has led to the identification and characterization of numerous NK cell subsets with unique activity and antiviral (and anti-tumor) potential.

Area(s) of Focus:
Autoimmunity
Cancer Immunology 

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Alice O. Kamphorst is an Assistant Professor at the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. She received her PhD from The Rockefeller University, studying antigen presentation and dendritic cell biology with the mentorship of Michel Nussenzweig. In her post-doctoral studies, Alice worked on T cells and PD-1 immunotherapy with Rafi Ahmed at Emory University.

The Kamphorst lab focuses on T cell differentiation with a specific interest on situations of chronic antigen stimulation, such as in cancer. The research program aims to determine how inflammation, costimulation and other factors in the microenvironment influence CD8 T cell differentiation, dysfunction and rescue by immunotherapy. To address those questions the lab uses mouse models of chronic viral infection and tumor, as well as analysis of samples from cancer patients. The lab has a deep interest on how adaptive immune responses are modulated and on interventional strategies that can be used to improve human health. Understanding the factors that govern T cell differentiation and function will enable the identification of targetable molecules and pathways to improve the efficacy of immunotherapy.

Area(s) of Focus:
Cancer Immunology

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Dr. Sergio Lira received his MD from the Universidade Federal de Pernambuco in Brazil (1982) and his PhD in Physiology and Pharmacology from the University of California at San Diego (1988). He did his postdoctoral training at the Roche Institute for Molecular Biology in Nutley, NJ. After his postdoctoral training he worked for 11 years in the pharma sector, first at Bristol-Myers Squibb (1992-1996) and then at Schering-Plough (1996-2002). Dr Lira joined Mount Sinai in 2002 as the Irene Diamond Associate Professor of Immunology. In 2007 he became the co-Director of the Immunology Institute (with Dr. Lloyd Mayer), and in 2013 was promoted to Director, a position he occupied until 2016. He is currently The Leona M. and Harry B. Hemsley Charitable Trust Professor of Immunology. His research focuses on the role of immune cells and the microbiome in mucosal inflammation and cancer. He has organized international meetings in this field, including the 2003 Keystone Symposium on Chemokines and the 2006 Gordon Research Conference on Chemotactic Cytokines. He was elected to the Henry Kunkel Society in 2006 and to the Association of American Physicians in 2008. Dr. Lira was a Visiting Professor at the Southern Medical University in Guangzhou, China (2013-2016) and is a member of the Board of Scientific Counselors of the National Cancer Institute (2013-present).

Area(s) of Focus:
Inflammatory Bowel Disease
Autoimmunity
Cancer Immunology
Microbiome
Skin Inflammatory Disease

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Thomas Marron, MD, PhD

Thomas Marron, MD, PhD is the Assistant Director of Early Phase and Immunotherapy Clinical Trials for the Tisch Cancer Institute, and Assistant Professor of Medicine at the Icahn School of Medicine at Mount Sinai. Dr. Marron’s previous work focused on studying innate immune signaling pathways, such as Toll-like receptors (TLRs), in primary immunodeficiencies; he now studies the role of agents targeting TLRs and other inflammatory pathways in cancer, specifically how they can be harnessed as part of in situ vaccines. He oversees an immunotherapy clinical trials program in the Tisch Cancer Institute which focuses on human cancer vaccines and novel combinatorial immunotherapy approaches. He also leads neoadjuvant trials in multiple tumor types aimed at characterizing the dynamic effects of immunotherapy, chemotherapy, and emerging immunomodulatory compounds on the tumor microenvironment, in order to identify biomarkers of response or resistance, and plan rational combinatorial prospective approaches to investigate in the pre-clinical and early-phase clinical setting.

Area(s) of focus:
Cancer Immunology

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Miriam Merad, MD, PhD is the Icahn School of Medicine at Mount Sinai Chair Professor in Cancer Immunology and the Director of the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai in New York. Dr. Merad obtained her MD at the University of Algiers, Algeria. She did her residency in Hematology and Oncology in Paris, France and obtained her PhD in immunology in collaboration between Stanford University and University of Paris VII. She was recruited to the Icahn School of Medicine at Mount Sinai in 2004 and was promoted to the rank of Associate Professor with Tenure in 2007 and to Full Professor in 2010 and in 2014, she obtained an Endowed Chair Professor in Cancer Immunology.

Dr. Merad’s laboratory studies the contribution of macrophages and dendritic cells to Cancer and Inflammatory disease in mice and Human. Dr. Merad’s pioneering work mapping the regulatory network of dendritic cells (DCs) resulted in identification of a lineage of DC, the CD103+ DC, that is now considered a key target to improve antiviral and antitumor immunity. Another of her key discoveries is that, contrary to the previously-held beliefs that monocytes are precursors of macrophages, she found that tissue-resident macrophages in fact arise from embryonic precursors that take residence in tissues prior to birth and are maintained independently of adult hematopoiesis. These insights are now being used to develop novel macrophage and dendritic cell-specific targets for the treatment of Cancer and Inflammatory diseases. 

Dr. Merad has authored more than 160 primary papers and reviews in high profile journals. Dr. Merad receives generous funding from the National Institutes of Health (NIH) for her research on innate immunity and their contribution to human disease, and belongs to several NIH consortia. She is an elected member of the American Society of Clinical Investigation and lectures around the world on her work. 

Area(s) of Focus:
Cancer Immunology
Inflammatory Bowel Disease
Neuroimmunology 

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Thomas M. Moran, PhD is the Director of the Center for Therapeutic Antibody Development (CTAD) at the Icahn School of Medicine at Mount Sinai. The Center within the Drug Discovery Institute produces monoclonal antibodies against target that include infectious agents, cell receptors, secreted proteins, and cell surface markers. CTAD is a cutting edge monoclonal antibody facility and has established collaboration with Regeneron Pharmaceuticals to use the Velocimmune mice to produce mAb for some projects. This second generation humanized mouse is superior to previous versions in that the mouse constant regions allow interaction with mouse immune elements leading to stronger humoral responses. Dr. Moran has published widely on immunity to virus infection using both mouse models and studies using samples from human subjects. He served as the overall director of the NIH funded Center for Investigating Viral Immunity and Antagonism (CIVIA) that focused on studies of human immunology and infectious disease by advancing technological methodologies, supporting inventive research, serving as a conduit for collaboration. Dr. Moran was PI for the now concluded Viral Immunity in Pregnancy study (VIP). This was a study of changes that occur in women during pregnancy with an emphasis on understanding their enhanced susceptibility to infection.

CTAD works in all the areas of interest aimed at developing therapeutic monoclonal antibodies. Currently projects in Cancer, Infectious Disease, Autoimmunity and Neuroimmunology are being pursued.

Area(s) of Focus:
Cancer Immunology
Microbiome and Host Pathogen Interaction
Autoimmunity
Neuroimmunology

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Jordi Ochando, PhD is an Assistant Professor of Oncological Sciences and Director of the Flow Cytometry CoRE at the Icahn School of Medicine at Mount Sinai. The Ochando laboratory investigates the origin, development, and immune function of macrophages in organ transplantation. His laboratory has recently discovered that trained immunity represents a previously unrecognized pathway that mediates allograft rejection. To prevent the detrimental effects of trained macrophages, the Ochando laboratory developed a novel revolutionary targeted therapeutic delivery approach in which drug-loaded nanobiologics that specifically target macrophages in vivo and induce long-term allograft acceptance. This research represents a compelling framework for developing novel targeted therapies that promote immunological tolerance.

Area(s) of Focus:
Transplant 

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Hélène Salmon, PhD is an Assistant Professor of Oncological Sciences. Dr. Salmon’s group studies the contribution of stromal cells to tumor immunity, with a particular focus on cancer-associated fibroblasts (CAFs). Using dynamic imaging in human tumor tissue, her research identified the stromal extracellular matrix as a key regulator of T cell motility and distribution at the tumor site. Her team is now investigating strategies to target CAFs and CAF molecules and increase tumor response to current immunotherapies. In addition to preclinical animal models of cancer, Dr. Salmon’s group studies stromal cell biology in fresh tumor samples from lung cancer patients. Her projects aim at understanding the fibroblast-immune cell crosstalk at the tumor site.

Area(s) of Focus:
Cancer Immunology 

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Headshot of Robert Samstein, MD, PhD

Robert Samstein, MD, PhD is a Radiation Oncologist in the Department of Radiation Oncology at Mount Sinai and a physician scientist with a laboratory in the Precision Immunology Institute at the Icahn School of Medicine at Mount Sinai. Dr. Samstein completed his graduate work with Alexander Rudensky studying the development and function of regulatory T cells. He completed his transitional year internship and residency in Radiation Oncology at Memorial Sloan Kettering Cancer Center in New York, NY. During residency, he conducted laboratory research with Dr. Timothy Chan investigating predictors of response to immunotherapy as part of the American Board of Radiology Holman Research pathway.

Dr. Samstein’s research interests are focused on understanding the interaction between the patient’s immune system and cancer cells in the tumor, elucidating the role of the DNA damage repair and response pathways in altering the tumor’s ability to be recognized and attacked by the immune system. His laboratory will work to identify new strategies to harness the immune anti-tumor response and expand the therapeutic window of traditional immunotherapies.

Area(s) of Focus:
Cancer Immunology
Autoimmunity

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Adrian Ting, PhD is an Associate Professor of Medicine/Immunology. His lab studies how ubiquitination affects cellular survival and death, as well as inflammatory signaling pathways. The lab discovered that non-degradative K63-linked polyubiquitination of the signaling molecule RIPK1, or the lack thereof, determines whether cell survival or cell death ensues in response to TNF. Ubiquitination of RIPK1 serves to function as an early cell death checkpoint in TNF signaling and blocking this process leads to apoptosis and necroptosis. Central to converting RIPK1 to a death-signaling molecule is its upstream regulator CYLD, a tumor suppressor and a deubiquitinating enzyme that preferentially removes K63-linked polyubiquitin chains from RIPK1. In recent years, the lab has shifted its focus to post-translational mechanisms (PTM) that inhibit CYLD, which has to be kept inactive to prevent inappropriate cell death. These inhibitory PTM include phosphorylation, proteolysis and degradation. Disruption of these inhibitory mechanisms led to excessive CYLD/RIPK1-mediated cell death and inflammation in multiple tissues including the skin, lung, and liver. The role of this CYLD-mediated cell death in physiological responses to microbial infections is currently under investigation. Furthermore, the role of this cell death in pathologies such as inflammatory disorders, transplantation and cancer are also under investigation. The goal of the lab is to thoroughly characterize the regulation and function of this cell death pathway so that rationally designed drugs can be developed to disrupt it for therapeutic purposes.

Area(s) of Focus:
Cancer Immunology
Immunodeficiency
Skin Inflammatory Diseases
Transplant 

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Huabao Xiong, MD, PhD is an Associate Professor of Medicine/Immunology. The Xiong lab studies the functions of Interferon Regulatory Factor 8 (IRF-8) expressed in different immune cells in the regulation of immune responses. They study the regulation of T helpers by IRF8 in the development of inflammatory bowel diseases; reprograming of macrophage polarization by IRF-8 in host defense against intracellular bacterial infection; modulation of MDSCs by IRF-8 in tumor development. They also study the functions of nitric oxide (NO) produced by T cells in the regulation of T helper cell development and the contribution of T cell-derived iNOS in the development of intestinal inflammation. The laboratory is dedicated to understanding the transcriptional regulation in the development of inflammatory bowel diseases.

The research direction includes:

  • Transcriptional regulation of Th17 cells in the development of intestinal inflammation.
  • Molecular mechanisms for the regulation of proinflammatory M1 macrophages in inflammatory diseases.
  • Identification of novel therapeutic targets for suppression of Th17 cells and M1 macrophages for the therapeutic purposes.

Area(s) of Focus:
Inflammatory Bowel Diseases 

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