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The Dysregulation of T Follicular Regulatory Cells in a Mouse Model of Glioblastoma Multiforme Leads to Humoral Immune Dysfunction

By Long Hoang Dao

Abstract

Glioblastoma multiforme (GBM) is a highly lethal cancer arising from mutations in glial cells. Many therapies currently in development for this disease focus on the role of the immune system and its inability to interact with the tumor. One of the reasons for its poor prognosis is its ability to evade the immune system. This is accomplished by the upregulation of Foxp3^+ T regulatory cells (Tvregs), a T cell subset that is capable of potent immunosuppression. This subset of cells has long been characterized in glioblastoma and many other cancers. In this dissertation, we outline how a newer subset of Tvregs, T follicular regulatory cells (Tvfr cells) are capable of controlling the humoral immune response within GBM. In the healthy body, this subset of cells is responsible for terminating germinal center (GC) responses following infection. In particular, Tvfr cells function by limiting the number of available CXCR5^+ T follicular helper cells (Tvfh cells) and GC B cells in vivo. We demonstrate that the amount of Tvfr cells that contribute to the total pool of CXCR5^+ cells is increased in the dural lymphatic vessels, a lymphatic vessel that remains uncharacterized in GBM, of immunocompetent GBM tumor-bearing mice following infection with Complete Freund’s Adjuvant. We additionally show that Tvfh function is inhibited in these GBM model mice, as they are impaired in their ability to display CD40L, a surface marker that is crucial to the formation of GCs and, thus, antibodymediated immune responses. We further show that the downstream generation of antibody-producing plasma cells is inhibited in these tumor-bearing mice. We also show that these Tvreg cells in GBM under inflammatory conditions appear to be of extrathymic rather than thymic origins. We additionally show that treatment with PD-L1 monoclonal antibody (mAb) is capable of preventing the expansion of Tvfr cells and is capable of rescuing the development of plasmablasts and plasma cells in tumor-bearing mice. Finally, we show that addition of PD-L1 mAb is capable of slightly extending the survival time of tumor bearing mice when paired with CFA treatment. When taken together, these results show that a profound dysfunction exists in the humoral immune system of this GBM mouse model and can be rescued with PD-L1 blockade

Topics: Glioblastoma, T Regulatory, T Follicular Helper, T Follicular Regulatory, Immunosuppression, Humoral Immune Response, Cancer
Year: 2019
OAI identifier: oai:oaktrust.library.tamu.edu:1969.1/174111

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