Yiping Yang
Overview:
The goal of Dr. Yang’s laboratory is to understand the molecular and cellular mechanisms leading to the generation of potent and long-lasting anti-tumor immunity, and to develop effective gene immunotherapeutic strategies for treating cancer. Furthermore, rational pre-clinical approaches will be tested in clinical trials in patients with Epstein-Barr virus (EBV)-related malignancies. Specifically, we focus on the following areas:
1. Innate Immunity to Viruses. Recombinant vaccinia virus and adenovirus have been developed as potent vaccine vehicles for treating cancer and infectious diseases. Recent studies have shown that the unique potency of these viruses lies in their effective activation of the innate immune system. How these viruses activate the innate immune system remains largely unknown. We have been interested in the role of pattern-recognition receptors including Toll-like receptors (TLRs)in innate immune recognition of these viruses as well as their signaling pathways. In addition, we are investigating the role of innate immune cells such as natural killer (NK) cells in innate and adaptive immune responses to these viruses. A full understanding of these processes will help us design effective vaccine strategies.
2. T Cell Memory. Eliciting long-lived memory T cell response is an ultimate goal of vaccination to provide long-term immunity against cancer. However, it is not clear what controls the formation of long-lived memory T cells. The understanding of mechanisms underlying memory T cell formation will provide important insights into the design of effective vaccines for treating cancer.
3. Regulatory T Cell Biology. Accumulating evidence has shown that the immunosuppressive CD4+CD25+Foxp3+ regulatory T cells (TReg) play a critical role in the suppression of anti-tumor immunity. However, little is known about how TReg suppress T cell activation in vivo. Delineation of mechanisms underlying TReg-mediated suppression in vivo will help develop strategies to overcome TReg-mediated suppression in favor of boosting anti-tumor immunity.
4. Immunotherapy for EBV-associated Malignancies. Clinically, EBV-associated malignancies such as Hodgkin’s lymphoma offer a unique model to explore antigen-defined immunotherapy approaches because EBV-derived tumor antigens are specific for tumor cells only. Using this clinical model, we will test the utility of rational strategies identified in our preclinical models.
1. Innate Immunity to Viruses. Recombinant vaccinia virus and adenovirus have been developed as potent vaccine vehicles for treating cancer and infectious diseases. Recent studies have shown that the unique potency of these viruses lies in their effective activation of the innate immune system. How these viruses activate the innate immune system remains largely unknown. We have been interested in the role of pattern-recognition receptors including Toll-like receptors (TLRs)in innate immune recognition of these viruses as well as their signaling pathways. In addition, we are investigating the role of innate immune cells such as natural killer (NK) cells in innate and adaptive immune responses to these viruses. A full understanding of these processes will help us design effective vaccine strategies.
2. T Cell Memory. Eliciting long-lived memory T cell response is an ultimate goal of vaccination to provide long-term immunity against cancer. However, it is not clear what controls the formation of long-lived memory T cells. The understanding of mechanisms underlying memory T cell formation will provide important insights into the design of effective vaccines for treating cancer.
3. Regulatory T Cell Biology. Accumulating evidence has shown that the immunosuppressive CD4+CD25+Foxp3+ regulatory T cells (TReg) play a critical role in the suppression of anti-tumor immunity. However, little is known about how TReg suppress T cell activation in vivo. Delineation of mechanisms underlying TReg-mediated suppression in vivo will help develop strategies to overcome TReg-mediated suppression in favor of boosting anti-tumor immunity.
4. Immunotherapy for EBV-associated Malignancies. Clinically, EBV-associated malignancies such as Hodgkin’s lymphoma offer a unique model to explore antigen-defined immunotherapy approaches because EBV-derived tumor antigens are specific for tumor cells only. Using this clinical model, we will test the utility of rational strategies identified in our preclinical models.
Positions:
Professor of Medicine
Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine
Professor of Immunology
Immunology
School of Medicine
Member of the Duke Cancer Institute
Duke Cancer Institute
School of Medicine
Education:
M.D. 1985
Zhejiang University (China)
Ph.D. 1993
University of Michigan at Ann Arbor
Residency, General Internal Medicine
University of Pennsylvania School of Medicine
Fellowship, Medical Oncology
Johns Hopkins University School of Medicine
Grants:
Role of hedgehog signaling in tumor-associated macrophage polarization
Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date
T memory stem cells in cancer
Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date
Novel Strategies for Cancer Immunotherapy in Stem Cell Transplant
Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date
Role of Endogenous Toll-Like Receptor Ligands in Allospecific T Cell Activation
Administered By
Surgery, Abdominal Transplant Surgery
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date
Role of inflammation in cancer progression
Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date
Publications:
Heparan sulfate is a plasma biomarker of acute cellular allograft rejection.
Despite advances in management of immunosuppression, graft rejection remains a significant clinical problem in solid organ transplantation. Non-invasive biomarkers of graft rejection can facilitate earlier diagnosis and treatment of acute rejection. The purpose of this study was to investigate the potential role of heparan sulfate as a novel biomarker for acute cellular rejection. Heparan sulfate is released from the extracellular matrix during T-cell infiltration of graft tissue via the action of the enzyme heparanase. In a murine heart transplant model, serum heparan sulfate is significantly elevated during rejection of cardiac allografts. Moreover, expression of the enzyme heparanase is significantly increased in activated T-cells. In human studies, plasma heparan sulfate is significantly elevated in kidney transplant recipients with biopsy-proven acute cellular rejection compared to healthy controls, recipients with stable graft function, and recipients without acute cellular rejection on biopsy. Taken together, these findings support further investigation of heparan sulfate as a novel biomarker of acute cellular rejection in solid organ transplantation.
MLA Citation
Barbas, Andrew S., et al. “Heparan sulfate is a plasma biomarker of acute cellular allograft rejection..” Plos One, vol. 13, no. 8, 2018. Pubmed, doi:10.1371/journal.pone.0200877.
URI
https://scholars.duke.edu/individual/pub1338728
PMID
30086133
Source
pubmed
Published In
Plos One
Volume
13
Published Date
Start Page
e0200877
DOI
10.1371/journal.pone.0200877
Jak3 Dependent Inhibition of Alloreactive T Cell Proliferation in the Setting of Chronic TLR Stimulation.
MLA Citation
Brennan, T., et al. “Jak3 Dependent Inhibition of Alloreactive T Cell Proliferation in the Setting of Chronic TLR Stimulation..” American Journal of Transplantation, vol. 13, 2013, pp. 256–256.
URI
https://scholars.duke.edu/individual/pub952547
Source
wos-lite
Published In
American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons
Volume
13
Published Date
Start Page
256
End Page
256
NKG2D is required for NK cell activation and function in response to E1-deleted adenovirus.
Despite high transduction efficiency in vivo, the application of recombinant E1-deleted adenoviral vectors for in vivo gene therapy has been limited by the attendant innate and adaptive immune responses to adenoviral vectors. NK cells have been shown to play an important role in innate immune elimination of adenoviral vectors in vivo. However, the mechanisms underlying NK cell activation and function in response to adenoviral vectors remain largely undefined. In this study, we showed that NK cell activation upon adenoviral infection was dependent on accessory cells such as dendritic cells and macrophages and that cell contact-dependent signals from the accessory cells are necessary for NK cell activation. We further demonstrated that ligands of the NK activating receptor NKG2D were upregulated in accessory cells upon adenoviral infection and that blockade of NKG2D inhibited NK cell activation upon adenoviral infection, leading to a delay in adenoviral clearance in vivo. In addition, NKG2D was required for NK cell-mediated cytolysis on adenovirus-infected targets. Taken together, these results suggest that efficient NK cell activation and function in response to adenoviral infection is critically dependent on the NKG2D pathway, which understanding may assist in the design of effective strategies to improve the outcome of adenovirus-mediated gene therapy.
MLA Citation
Zhu, Jiangao, et al. “NKG2D is required for NK cell activation and function in response to E1-deleted adenovirus..” J Immunol, vol. 185, no. 12, Dec. 2010, pp. 7480–86. Pubmed, doi:10.4049/jimmunol.1002771.
URI
https://scholars.duke.edu/individual/pub777564
PMID
21076062
Source
pubmed
Published In
J Immunol
Volume
185
Published Date
Start Page
7480
End Page
7486
DOI
10.4049/jimmunol.1002771
CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses.
The role of CD4 T cell help in primary and secondary CD8 T cell responses to infectious pathogens remains incompletely defined. The primary CD8 T response to infections was initially thought to be largely independent of CD4 T cells, but it is not clear why some primary, pathogen-specific CD8 T cell responses are CD4 T cell dependent. Furthermore, although the generation of functional memory CD8 T cells is CD4 T cell help dependent, it remains controversial when the "help" is needed. In this study, we demonstrated that CD4 T cell help was not needed for the activation and effector differentiation of CD8 T cells during the primary response to vaccinia virus infection. However, the activated CD8 T cells showed poor survival without CD4 T cell help, leading to a reduction in clonal expansion and a diminished, but stable CD8 memory pool. In addition, we observed that CD4 T cell help provided during both the primary and secondary responses was required for the survival of memory CD8 T cells during recall expansion. Our study indicates that CD4 T cells play a crucial role in multiple stages of CD8 T cell response to vaccinia virus infection and may help to design effective vaccine strategies.
MLA Citation
Novy, Patricia, et al. “CD4 T cells are required for CD8 T cell survival during both primary and memory recall responses..” J Immunol, vol. 179, no. 12, Dec. 2007, pp. 8243–51. Pubmed, doi:10.4049/jimmunol.179.12.8243.
URI
https://scholars.duke.edu/individual/pub777575
PMID
18056368
Source
pubmed
Published In
The Journal of Immunology
Volume
179
Published Date
Start Page
8243
End Page
8251
DOI
10.4049/jimmunol.179.12.8243
Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy.
Recombinant adenoviruses with E1 sequences deleted efficiently transfer genes into a wide variety of target cells. Antigen- and nonantigen-specific responses to the therapy lead to toxicity, loss of transgene expression, and difficulties with vector readministration. We have created new cell lines that allowed the isolation of more disabled adenovirus vectors that have both E1 and E4 deletions. Studies with murine models of liver-directed gene therapy indicated that the E1- and E4-deleted vector expresses fewer virus proteins and induces less apoptosis, leading to blunted host responses and an improved safety profile. The impact of the E4 deletion on the stability of vector expression was confounded by immune responses to the transgene product, which in this study was beta-galactosidase. When transgene responses were eliminated, the doubly deleted vector was substantially more stable in mouse liver than was the E1-deleted construct. These studies indicate that adenovirus vectors with both E1 and E4 deletions may have advantages in terms of safety and efficacy over first-generation constructs for liver-directed gene therapy.
Authors
Gao, GP; Yang, Y; Wilson, JM
MLA Citation
Gao, G. P., et al. “Biology of adenovirus vectors with E1 and E4 deletions for liver-directed gene therapy..” J Virol, vol. 70, no. 12, Dec. 1996, pp. 8934–43.
URI
https://scholars.duke.edu/individual/pub807236
PMID
8971023
Source
pubmed
Published In
Journal of Virology
Volume
70
Published Date
Start Page
8934
End Page
8943
Research Areas:
Acute Disease
Adaptive Immunity
Adenoviridae
Adenoviridae Infections
Adenovirus E1A Proteins
Adenovirus E1B Proteins
Adenoviruses, Human
Adjuvants, Immunologic
Adoptive Transfer
Aged
Alternative Splicing
Antibody Formation
Antigen Presentation
Antigens, CD4
Antigens, CD8
Antigens, Neoplasm
Antigens, Viral
Antineoplastic Agents
Autoantigens
Autoimmune Diseases
Autoimmunity
Blotting, Western
CD4 Antigens
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Cell Proliferation
Chaperonins
Chloride Channels
Coculture Techniques
Combined Modality Therapy
Cyclic AMP
Cystic Fibrosis Transmembrane Conductance Regulator
Cytokines
Cytotoxicity, Immunologic
DNA, Viral
Dendritic Cells
Dependovirus
Disease Models, Animal
Electric Conductivity
Endoplasmic Reticulum
Endosomes
Extracellular Signal-Regulated MAP Kinases
Female
Flow Cytometry
Gene Deletion
Gene Knock-In Techniques
Gene Transfer Techniques
Gene therapy
Genes, Bacterial
Genes, Viral
Genetic Therapy
Germinal Center
Glucose
Graft vs Host Disease
Growth Inhibitors
HLA Antigens
HLA-C Antigens
Heat-Shock Proteins
Hemagglutinins
Hematologic Neoplasms
Hematopoietic Stem Cell Transplantation
Heparitin Sulfate
Histocompatibility
Histocompatibility Testing
Humans
Immune System
Immune Tolerance
Immunity, Cellular
Immunity, Innate
Immunologic Memory
Immunosuppressive Agents
Immunotherapy
Influenza A virus
Interferon Type I
Interferon-beta
Interleukin-10
Interleukin-12
Interleukin-13
Interleukin-2
Interleukin-6
Killer Cells, Natural
Luciferases
Lung Neoplasms
Lymphocyte Activation
Lymphocyte Depletion
Lymphocyte Transfusion
Lymphocytes
Lymphoma
Lymphopenia
Macrophages
Male
Membrane Glycoproteins
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Knockout
Mice, Mutant Strains
Mice, Nude
Mice, Transgenic
Microsomes
Middle Aged
Mitosis
Molecular Sequence Data
Myelodysplastic Syndromes
Myeloid Cells
Myeloid Differentiation Factor 88
NK Cell Lectin-Like Receptor Subfamily K
Neoplasms
North Carolina
Oocytes
Peripheral Blood Stem Cell Transplantation
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
RNA, Messenger
Receptors, Cell Surface
Receptors, Interleukin-1
Receptors, KIR
Recombinant Proteins
Retrospective Studies
Reverse Transcriptase Polymerase Chain Reaction
Risk Factors
STAT1 Transcription Factor
Sequence Deletion
Stem Cell Transplantation
Survival Rate
T-Cell Antigen Receptor Specificity
T-Lymphocytes
T-Lymphocytes, Cytotoxic
T-Lymphocytes, Regulatory
Toll-Like Receptor 2
Toll-Like Receptor 4
Toll-Like Receptor 8
Toll-Like Receptor 9
Toll-Like Receptors
Transfection
Transgenes
Transplantation Conditioning
Transplantation, Homologous
Tumor Escape
Vaccines
Vaccinia
Vaccinia virus
Virus Diseases
Viruses
Xenopus
beta-Galactosidase
Professor of Medicine
Contact:
2019 MSRB 2, 106 Research Drive, Durham, NC 27710
Duke Box 103005, Durham, NC 27710