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Abstract

The lymphatic system is the main transport route for fluid, antigens, exosomes, and immune cells from peripheral tissues to the lymph nodes (LNs). Lymphatics pervade all tissues and surround the LN capsule as well as penetrating into the T cell zone. Lymphangiogenesis, or lymphatic vessel proliferation, is a process dependent on the VEGF-C/VEGFR-3 axis. The first part of this thesis elucidates the role of the VEGF-C/VEGFR-3 axis in modulating vaccine outcomes and immunotherapy efficacy in cancer. In the second part of this thesis, I will assess the mechanisms of action of collagen-binding cytokines for cancer immunotherapy. Chapter 1 introduces to the main concepts contained within this thesis, including a description of the lymphatic system as well as known functions of lymphatic endothelial cells (LECs). I furthermore explore other key concepts such as cancer immunotherapy and characteristics of a vaccine response, including antibody subclasses and their distinct functions. In Chapter 2, I explore how the VEGF-C/VEGFR-3 axis modulates the vaccine response. I observe that the VEGFR-3 axis modulates type 2 immunity, specifically through regulation of cytokine secretion by T cells and downstream IgG1 class switch, and this affect was dependent on LEC MHC II. Chapter 3 elucidates mechanisms by which intratumoral lymphatics in VEGF-C overexpressing melanomas potentiate immunotherapy efficacy. Here I determine that LEC derived CXCL9 and the CXCR3 axis are critical for driving therapeutic efficacy in an adoptive cell transfer immunotherapy model. Chapter 4 explores the mechanisms of action of two distinct collagen-binding domain (CBD) cytokine therapies that were combined with CBD-IL-12 to form distinct combinations with the toxic, but highly effective, IL-12. By combining IL-12 with other less toxic cytokines, GM-CSF and IL-7, the effective dose of IL-12 could be lowered dramatically without affected toxicity. I demonstrate that while both cytokines synergize excellently with CBD-IL-12, they have completely distinct mechanisms of action. Lastly, in Chapter 5 I discuss future directions for interesting and relevant avenues of exploration based on the novel work presented herein.

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