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Cederberg, Rachel Ann

University of British Columbia

The solid tumor microenvironment contains structural and cellular components that can dictate cancer progression and therapy response. These cellular components can include cells of the innate immune system, such as myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), and eosinophils, as well as cells of the adaptive immune system, including CD4⁺ T regulatory cells (Tregs) and cytotoxic CD8⁺ T cells. The aim of this thesis work is to interrogate the pro- and anti- tumorigenic roles myeloid cells play in primary and metastatic disease, and how these myeloid populations interact with cells of the adaptive immune system to influence anti-tumor immunity. In Chapter 2, I examined how proteins secreted by cancer cells can promote a tumor-permissive microenvironment through the recruitment of suppressive innate and adaptive immune cells to the lungs. I demonstrated that tumor cells secreted proteins that drove the recruitment and/or expansion of pulmonary TAMs, Tregs, and granulocytic-MDSCs (G-MDSCs), resulting in increased primary lung tumor growth and pulmonary metastasis of mammary carcinoma cells, respectively. Targeting tumor-secreted proteins, or the suppressive immune cells that are expanded in response to said proteins, led to a decrease in primary and metastatic pulmonary disease. In Chapter 3, I utilized several transgenic mouse models of eosinophilia and eosinophil-deficiency to assess the role of eosinophils in breast cancer pulmonary metastasis. I found that eosinophils were directly cytotoxic towards mammary carcinoma cells, likely through degranulation, and that eosinophils decreased pulmonary metastatic growth of breast cancer cells. In Chapter 4, I profiled the dynamic myeloid compartment following antigen specific CD8⁺ T cell-mediated tumor regression and recurrence. I demonstrated that using glucose restriction of CD8⁺ T cells in vitro led to improved tumor regression in vivo. I identified several potentially suppressive myeloid cell subsets, including TAMs and arginase-1ʰⁱ monocytic-MDSCs (M-MDSCs) that expand during CD8⁺ T cell-mediated tumor regression and subsequent recurrence, which may play a role in tumor regrowth. This thesis work aims to examine the diverse phenotype and function of myeloid cells in primary and metastatic disease, ultimately contributing to an improved understanding of the interplay between the innate and adaptive immune system in the solid tumor microenvironment.

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2023-06-22

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/85142

Pathology and Laboratory Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/