AbstractMonoclonal antibodies are an established modality for cancer treatment, however currently FDA approved treatments are designed using only one of the five antibody classes, IgG. Another antibody class, IgE, participates in allergic disease pathology, but also engenders immune protective functions from parasitic and bacterial infections. Several studies have demonstrated that tumour antigen specific IgE can engender different effector functions to those triggered by IgG. Moreover, monocytes, may play important roles in the anti-tumour efficacy of IgE. Thus, this Thesis examined the immune mediators associated with the anti-tumour functions of monocytes potentiated by tumour antigen specific IgE monoclonal antibodies.
IgE engagement with human monocytes via the IgE Fc regions, and with human tumour cells via the Fab regions could trigger cytotoxic killing of tumour cells. Monocytes from healthy volunteers, patients with ovarian cancer or patients with melanoma, were able to secrete Th1, Th2, Th17, anti-parasitic/infection associated immune mediators in response to IgE. IgE cross-linking on the surface of primary monocytes triggered upregulation of key protein kinases already reported to be found downstream of FcεRI in mast cells. These findings support the premise that monocytes are key immune effector cells which can be activated by IgE monoclonal antibodies to trigger different arms of immune responses and immune activating signals. Next, despite some differences in monocyte subset populations and their IgE Fc receptor expression in cancer patients, anti-tumour IgEs could bind and activate ovarian cancer and melanoma patient monocytes to trigger cancer cell cytotoxicity and secrete immune activating cytokines. When the association of intra-tumoural molecular expression of mediators with known or putative roles in protective or cancer-associated immunity were studied in relation to overall survival (OS) in ovarian cancer, it was demonstrated that: a) using a machine learning approach, these mediator profiles could distinguish ovarian cancer from non-malignant ovarian tissues, and b) higher intra-tumoural expression of some classical Th1, Th2, Th17, antiparasitic/ infection and M1-macrophage mediator signatures were associated with better 5-year OS in ovarian cancer. In contrast, higher intra-tumoural expression of inflammatory and pro-angiogenic markers resulted in either no effect to survival or were associated with lower 5-year OS. However, when these inflammatory and angiogenic mediators were combined with the beneficial mediators of Th1, Th2, Th17, anti-parasitic/infection clearance and M1-macrophage immunity, some negatively prognostic inflammatory and angiogenic markers were neutralized, or even rescued.
Overall, this Thesis demonstrates IgE-mediated immune activating functions and stimulation of monocytes which can trigger immune mediators associated with improved cancer patient survival. IgE may therefore confer anti-tumour functions not only through directly triggering effector cell-mediated killing of cancer cells, but also by enhancing immune-activating cytokines and chemokines. These could potentially counteract the effects of mediators with pro-tumour functions in the tumour microenvironment. Overall, this Thesis provides evidence that IgE monoclonal antibodies can activate key immune effector cells such as monocytes and trigger different arms of the human immune response to combat cancer. These attributes could contribute to the promise of IgE as a new candidate class for cancer immunotherapy.
|Date of Award
|1 Dec 2020
|Sophia Karagiannis (Supervisor), Katie E Lacy (Supervisor) & Sophia Tsoka (Supervisor)