| dc.description.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. | en |
