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.

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:

Benzene induces haematotoxicity by promoting deacetylation and autophagy.

Chronic exposure to benzene is known to be associated with haematotoxicity and the development of aplastic anaemia and leukaemia. However, the mechanism underlying benzene-induced haematotoxicity, especially at low concentrations of chronic benzene exposure has not been well-elucidated. Here, we found that increased autophagy and decreased acetylation occurred in bone marrow mononuclear cells (BMMNCs) isolated from patients with chronic benzene exposure. We further showed in vitro that benzene metabolite, hydroquinone (HQ) could directly induce autophagy without apoptosis in BMMNCs and CD34+ cells. This was mediated by reduction in acetylation of autophagy components through inhibiting the activity of acetyltransferase, p300. Furthermore, elevation of p300 expression by Momordica Antiviral Protein 30 Kd (MAP30) or chloroquine reduced HQ-induced autophagy. We further demonstrated that in vivo, MAP30 and chloroquine reversed benzene-induced autophagy and haematotoxicity in a mouse model. Taken together, these findings highlight increased autophagy as a novel mechanism for benzene-induced haematotoxicity and provide potential strategies to reverse this process for therapeutic benefits.
Authors
Qian, S; Han, Y; Shi, Y; Xu, W; Zhu, Y; Jiang, S; Chen, Y; Yu, Z; Zhang, S; Yang, Y; Yu, K; Zhang, S
MLA Citation
Qian, Shanhu, et al. “Benzene induces haematotoxicity by promoting deacetylation and autophagy..” J Cell Mol Med, vol. 23, no. 2, Feb. 2019, pp. 1022–33. Pubmed, doi:10.1111/jcmm.14003.
URI
https://scholars.duke.edu/individual/pub1357115
PMID
30411500
Source
pubmed
Published In
Journal of Cellular and Molecular Medicine
Volume
23
Published Date
Start Page
1022
End Page
1033
DOI
10.1111/jcmm.14003

Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) with donor lymphocyte infusion is the mainstay of treatment for many types of hematological malignancies, but the therapeutic effect and prevention of relapse is complicated by donor T-cell recognition and attack of host tissue in a process known as graft-versus-host disease (GvHD). Cytotoxic myeloablative conditioning regimens used prior to Allo-HSCT result in the release of endogenous innate immune activators that are increasingly recognized for their role in creating a pro-inflammatory milieu. This increased inflammatory state promotes allogeneic T-cell activation and the induction and perpetuation of GvHD. Here, we review the processes of cellular response to injury and cell death that are relevant following Allo-HSCT and present the current evidence for a causative role of a variety of endogenous innate immune activators in the mediation of sterile inflammation following Allo-HSCT. Finally, we discuss the potential therapeutic strategies that target the endogenous pathways of innate immune activation to decrease the incidence and severity of GvHD following Allo-HSCT.
Authors
Brennan, TV; Rendell, VR; Yang, Y
MLA Citation
Brennan, Todd V., et al. “Innate immune activation by tissue injury and cell death in the setting of hematopoietic stem cell transplantation..” Front Immunol, vol. 6, 2015. Pubmed, doi:10.3389/fimmu.2015.00101.
URI
https://scholars.duke.edu/individual/pub1062046
PMID
25852683
Source
pubmed
Published In
Frontiers in Immunology
Volume
6
Published Date
Start Page
101
DOI
10.3389/fimmu.2015.00101

Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection.

CD4 T cell help plays an important role in promoting CD8 T cell immunity to pathogens. In models of infection with vaccinia virus (VV) and Listeria monocytogenes, CD4 T cell help is critical for the survival of activated CD8 T cells during both the primary and memory recall responses. Still unclear, however, is how CD4 T cell help promotes CD8 T cell survival. In this study, we first showed that CD4 T cell help for the CD8 T cell response to VV infection was mediated by IL-21, a cytokine produced predominantly by activated CD4 T cells, and that direct action of IL-21 on CD8 T cells was critical for the VV-specific CD8 T cell response in vivo. We next demonstrated that this intrinsic IL-21 signaling was essential for the survival of activated CD8 T cells and the generation of long-lived memory cells. We further revealed that IL-21 promoted CD8 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 pathways and subsequent upregulation of the prosurvival molecules Bcl-2 and Bcl-x(L). These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies.
Authors
Novy, P; Huang, X; Leonard, WJ; Yang, Y
MLA Citation
Novy, Patricia, et al. “Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection..” J Immunol, vol. 186, no. 5, Mar. 2011, pp. 2729–38. Pubmed, doi:10.4049/jimmunol.1003009.
URI
https://scholars.duke.edu/individual/pub777563
PMID
21257966
Source
pubmed
Published In
J Immunol
Volume
186
Published Date
Start Page
2729
End Page
2738
DOI
10.4049/jimmunol.1003009

A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection.

Recent advances have suggested a crucial role of the innate immunity in shaping adaptive immune responses. How activation of innate immunity promotes adaptive T-cell responses to pathogens in vivo is not fully understood. It has been thought that Toll-like receptor (TLR)-mediated control of adaptive T-cell responses is mainly achieved by the engagement of TLRs on antigen-presenting cells to promote their maturation and function. In this study, we showed that direct TLR2-myeloid differentiating factor 88 (MyD88) signaling in CD8 T cells was also required for their efficient clonal expansion by promoting the survival of activated T cells on vaccinia viral infection in vivo. Effector CD8 T cells that lacked direct TLR2-MyD88 signaling did not survive the contraction phase to differentiate into long-lived memory cells. Furthermore, we observed that direct TLR2 ligation on CD8 T cells promoted CD8 T-cell proliferation and survival in vitro in a manner dependent on the phosphatidylinositol 3-kinase (PI3K)-Akt pathway activation and that activation of Akt controlled memory cell formation in vivo. These results identify a critical role for intrinsic TLR2-MyD88 signaling and PI3K-Akt pathway activation in CD8 T-cell clonal expansion and memory formation in vivo and could lead to the development of new vaccine approaches.
Authors
Quigley, M; Martinez, J; Huang, X; Yang, Y
MLA Citation
Quigley, Michael, et al. “A critical role for direct TLR2-MyD88 signaling in CD8 T-cell clonal expansion and memory formation following vaccinia viral infection..” Blood, vol. 113, no. 10, Mar. 2009, pp. 2256–64. Pubmed, doi:10.1182/blood-2008-03-148809.
URI
https://scholars.duke.edu/individual/pub777570
PMID
18948575
Source
pubmed
Published In
Blood
Volume
113
Published Date
Start Page
2256
End Page
2264
DOI
10.1182/blood-2008-03-148809

Transduction of dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers.

Immune responses to vector-corrected cells have limited the application of gene therapy for treatment of chronic disorders such as inherited deficiency states. We have found that recombinant adeno-associated virus (AAV) efficiently transduces muscle fibers in vivo without activation of cellular and humoral immunity to neoantigenic transgene products such as beta-galactosidase, which differs from the experience with recombinant adenovirus, where vibrant T-cell responses to the transgene product destroy the targeted muscle fibers. T cells activated following intramuscular administration of adenovirus expressing lacZ (AdlacZ) can destroy AAVlacZ-transduced muscle fibers, indicating a prior state of immunologic nonresponsiveness in the context of AAV gene therapy. Adoptive transfer of dendritic cells infected with AdlacZ leads to immune mediated elimination of AAVlacZ-transduced muscle fibers. AAVlacZ-transduced antigen-presenting cells fail to demonstrate beta-galactosidase activity and are unable to elicit transgene immunity in adoptive transfer experiments. These studies indicate that vector-mediated transduction of dendritic cells is necessary for cellular immune responses to muscle gene therapy, a step which AAV avoids, providing a useful biological niche for its use in gene therapy.
Authors
Jooss, K; Yang, Y; Fisher, KJ; Wilson, JM
MLA Citation
URI
https://scholars.duke.edu/individual/pub807231
PMID
9557710
Source
pubmed
Published In
Journal of Virology
Volume
72
Published Date
Start Page
4212
End Page
4223

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