A deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy... Show moreA deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy response has predominantly focused on T cells, however effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. By combining profiling of blood and tumors from metastatic breast cancer patients with mechanistic studies in mouse models, we uncovered the critical role of eosinophils in immunotherapy response, and we provide proof-of-principle for eosinophil engagement to enhance immunotherapy efficacy. Focusing on resistance mechanisms to immunotherapy, we demonstrate that neoadjuvant immunotherapy triggers persistent and systemic regulatory T cell activation which blunts therapeutic efficacy against metastatic spread of breast tumors. In addition, we demonstrate that neutrophils in the tumor microenvironment pose a barrier to immunotherapy response through T cell suppression. Lastly, we demonstrate that combining the immunomodulatory agent PD1-IL2v with cisplatin is a powerful approach to induce a broad activation of systemic and intratumoral adaptive and innate immunity, resulting in effective immunotherapy responses. Overall, this work identifies several key players and their interconnectivities in anti-tumor immunity and tumor-induced immunosuppression that may be therapeutically exploited to improve immunotherapy responses for breast cancer patients. Show less
Abnormal vascular physiology and precipitating inflammatory pathways underlie many different diseases, including hemorrhage, stroke, vascular dementia and even cancer. Pluripotent stem cells (PSCs)... Show moreAbnormal vascular physiology and precipitating inflammatory pathways underlie many different diseases, including hemorrhage, stroke, vascular dementia and even cancer. Pluripotent stem cells (PSCs) can now be derived by reprogramming from any individual so that it is possible in principle to derive all somatic cells of the human body that would normally be difficult to access. In this thesis, I studied the derivation of myeloid cells from human induced pluripotent stem cells (hiPSCs) to model the inflammatory component of vascular disease and characterized the development path of hiPSC-derived endothelial cells (hiPSC-ECs) which form the vascular walls. Functional defects in either of these cell types can cause or exacerbate vascular disease. I then used these cell types to gain insight into the mechanisms underlying two genetic diseases: Hereditary Hemorrhagic Telangiectasia (HHT) which is caused by mutations in a gene called Endoglin expressed on cells of the vascular wall and inflammatory macrophages, and a vascular tumor called Pseudomyogenic hemangioendothelioma (PHE) in which endothelial cells are thought to be the tumor cell of origin. I developed new differentiation protocols to generate inflammatory cells from hiPSC, characterized these cells functionally and used Next-Generation Sequencing and bioinformatic analysis to gain insight into the molecular pathways controlling development of one particular type of endothelial cells from hiPSC and the underlying tumorigenic mechanisms of PHE. Show less
