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A Call to the Arms: Regulation of T Cell Responses during EBV Infection and T Cell-Directed Immunotherapy of EBV-Associated Lymphomas


Schuhmachers, Patrick. A Call to the Arms: Regulation of T Cell Responses during EBV Infection and T Cell-Directed Immunotherapy of EBV-Associated Lymphomas. 2024, University of Zurich, Faculty of Science.

Abstract

The Epstein-Barr Virus (EBV) lists among the most successful human pathogens on earth. With its ability to transform human cells into long-lived cancer cells it contributes significantly to the prevalence of cancers worldwide and thus a deterioration in quality of life for many. In recent decades research on EBV has highlighted key points on how the immune system protects from lymphoproliferation and why this protection sometimes fails. Cytotoxic cells, particularly CD8+ T cells and NK cells, expand extensively after primary infection and are responsible for clearing the infection. The engagement of co-stimulatory molecules like CD244 constitutes an important mechanism of cytotoxic T cell activation and failure of doing so results in uncontrolled viral infection and, often, lymphoproliferation. XLP1 patients with defects in downstream signals of CD244 are highly susceptible to EBV infection. For them, primary infection often results in fulminant infectious mononucleosis with death rates reaching up to 65%. The first study presented in this thesis highlights how T cell responses are regulated by the engagement of co-stimulatory signaling via CD244 and its ligand CD48. Soluble CD48 suppressed naïve T cell expansion and the expression of activation markers in vitro and in vivo. Infected cells were identified as the major source of sCD48 in blood of tumor bearing and infected mice and correlated with the degree of tumor cell expansion and viral loads, respectively. Patients suffering from infectious mononucleosis or EBV+ lymphoproliferation presented with significantly elevated serum levels of sCD48 which is why one could consider sCD48 as an additional biomarker for the diagnosis of EBV associated diseases. The second study in this thesis focused on how T cells can be exploited for immunotherapy of EBV infection and EBV associated lymphomagenesis. To that end, a bi-specific CD20xCD3 T cell engaging antibody (CD20bsAb) was used to treat infected mice. The CD20bsAb was superior to Rituximab in depleting B cells in blood, spleen and bone marrow. It consequently conferred high protection against EBV-induced lymphomagenesis whereas Rituximab failed to do so. However, neither of the antibody therapies resulted in long-lasting protection. Discontinuation of CD20bsAb treatment after three doses resulted in rebound of viral infection and re-occurrence of lymphomas which is why a refinement of CD20bsAb treatment should be considered. Still, T cell engagement is effective in the treatment of EBV-associated lymphomagenesis and future treatments could consider a combinatory approach of sCD48 blockade and T cell engagement to treat EBV+ lymphomas.

Abstract

The Epstein-Barr Virus (EBV) lists among the most successful human pathogens on earth. With its ability to transform human cells into long-lived cancer cells it contributes significantly to the prevalence of cancers worldwide and thus a deterioration in quality of life for many. In recent decades research on EBV has highlighted key points on how the immune system protects from lymphoproliferation and why this protection sometimes fails. Cytotoxic cells, particularly CD8+ T cells and NK cells, expand extensively after primary infection and are responsible for clearing the infection. The engagement of co-stimulatory molecules like CD244 constitutes an important mechanism of cytotoxic T cell activation and failure of doing so results in uncontrolled viral infection and, often, lymphoproliferation. XLP1 patients with defects in downstream signals of CD244 are highly susceptible to EBV infection. For them, primary infection often results in fulminant infectious mononucleosis with death rates reaching up to 65%. The first study presented in this thesis highlights how T cell responses are regulated by the engagement of co-stimulatory signaling via CD244 and its ligand CD48. Soluble CD48 suppressed naïve T cell expansion and the expression of activation markers in vitro and in vivo. Infected cells were identified as the major source of sCD48 in blood of tumor bearing and infected mice and correlated with the degree of tumor cell expansion and viral loads, respectively. Patients suffering from infectious mononucleosis or EBV+ lymphoproliferation presented with significantly elevated serum levels of sCD48 which is why one could consider sCD48 as an additional biomarker for the diagnosis of EBV associated diseases. The second study in this thesis focused on how T cells can be exploited for immunotherapy of EBV infection and EBV associated lymphomagenesis. To that end, a bi-specific CD20xCD3 T cell engaging antibody (CD20bsAb) was used to treat infected mice. The CD20bsAb was superior to Rituximab in depleting B cells in blood, spleen and bone marrow. It consequently conferred high protection against EBV-induced lymphomagenesis whereas Rituximab failed to do so. However, neither of the antibody therapies resulted in long-lasting protection. Discontinuation of CD20bsAb treatment after three doses resulted in rebound of viral infection and re-occurrence of lymphomas which is why a refinement of CD20bsAb treatment should be considered. Still, T cell engagement is effective in the treatment of EBV-associated lymphomagenesis and future treatments could consider a combinatory approach of sCD48 blockade and T cell engagement to treat EBV+ lymphomas.

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Additional indexing

Item Type:Dissertation (cumulative)
Referees:Münz Christian, Metzner Karin, Oxenius Annette
Communities & Collections:04 Faculty of Medicine > Institute of Experimental Immunology
UZH Dissertations
Dewey Decimal Classification:610 Medicine & health
570 Life sciences; biology
Language:English
Place of Publication:Zürich
Date:14 May 2024
Deposited On:14 May 2024 12:34
Last Modified:14 May 2024 12:35
Number of Pages:140
OA Status:Closed