U01CA275306

Defining and Exploiting EBV-Infected Cell Heterogeneity in Non-Hodgkin Lymphomas

Epstein-Barr Virus (EBV) was the first human tumor virus discovered over 50 years ago in the context of endemic African Burkitt Lymphoma. However, we now know it is also a common herpesvirus that persists as a lifelong latent infection in virtually all adults worldwide.

Early work in the field led to a model for EBV infection promoting B-cell lymphomas as evidenced by the growth transformation, or immortalization, of primary resting human B cells into lymphoblastoid cell lines (LCLs). In vivo, EBV latent infection is met with a robust cytotoxic T-cell response, keeping most infected individuals protected from the oncogenic potential of the virus. As such, EBV-associated B-cell lymphomas occur at significantly higher rates in the setting of immune suppression.

Studies of viral and cellular gene expression in EBV-infected cells in vitro and in vivo have led to a model of lymphomagenesis characterized by the full expression of EBV latency gene products. However, the phenotypes in bulk culture and tumor tissue lack the nuanced detail of cellular heterogeneity and the consequences of minor frequency phenotypes on cancer progression.

Our recent single-cell RNAseq experiments have characterized gene expression within individual EBV-infected B cells, leading to an appreciation of cell fate trajectories and dynamic gene expression behavior of individual cells that we will integrate with human tumor analysis and mouse models of lymphomagenesis. It is our ultimate goal to define the importance of specific EBV-infected cell populations on the progression of B-cell non-Hodgkin lymphomas of the immune suppressed.

In this proposal, we aim to define how EBV-infected cell heterogeneity, including innate antiviral restriction and plasmablast differentiation, impacts lymphomagenesis and can be exploited for therapy. Our central hypothesis is that EBV-infected B cells toggle between different states that can restrict or promote lymphomagenesis, as well as render cells susceptible to virus-specific therapeutic intervention.

We formulated our central hypothesis based on preliminary data, including single-cell RNA sequencing of EBV-infected primary B cells early after infection and in LCLs, as well as characterization of cell fate dynamics regulating plasmablastic differentiation and lytic reactivation. We also provide evidence supporting a recent clinical trial using the "kick and kill" strategy of promoting EBV lytic reactivation with histone deacetylase inhibition coupled with ganciclovir to kill lymphoma cells that activate viral kinases.

Thus, the rationale for the proposed research is that understanding EBV regulation of infected B-cell fates will dissect mechanisms of pathogenesis and reveal new therapeutic avenues to target EBV-positive B-cell lymphomas. We plan to test our central hypothesis and complete the objectives in this proposal through the following three specific aims:

I) To define the role of innate immune sensors and effectors in EBV-mediated immortalization and lymphomagenesis.
II) To determine the role of plasmablast differentiation in suppressing EBV-mediated lymphomagenesis.
III) To define the mechanism by which HDAC inhibition promotes susceptibility of EBV+ DLBCL to killing by ganciclovir.

Duke University

TO PROVIDE FUNDAMENTAL INFORMATION ON THE CAUSE AND NATURE OF CANCER IN PEOPLE, WITH THE EXPECTATION THAT THIS WILL RESULT IN BETTER METHODS OF PREVENTION, DETECTION AND DIAGNOSIS, AND TREATMENT OF NEOPLASTIC DISEASES. CANCER BIOLOGY RESEARCH INCLUDES THE FOLLOWING RESEARCH PROGRAMS: CANCER CELL BIOLOGY, CANCER IMMUNOLOGY, HEMATOLOGY AND ETIOLOGY, DNA AND CHROMOSOMAL ABERRATIONS, TUMOR BIOLOGY AND METASTASIS, AND STRUCTURAL BIOLOGY AND MOLECULAR APPLICATIONS.

93.396 - Cancer Biology Research

National Cancer Institute (NCI) [HHS - NIH]

Durham, North Carolina 277103022 United States

Single Zip Code

The role of Epstein Barr virus (EBV) infection in Non-Hodgkin Lymphoma (NHL) and Hodgkin disease (HD) development with or without an underlying HIV infection (U01 Clinical Trial Optional) (PAR-21-348)

Amendment Since initial award the total obligations have increased 339% from $550,601 to $2,415,701.