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
Three aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation.... Show moreThree aspects of airway inflammation in asthma were investigated in this thesis: proof of concept, monitoring and management. In chapter 2 is shown that IL-5 is mainly effective in the circulation. In chapter 3 is shown that steroids improve airway hyperresponsiveness, sputum eosinophils, and NO. The changes were not related. This suggests that these markers may provide different information when monitoring anti-inflammatory treatment in asthma. In chapter 4 is shown that alpha-2-macroglobulin is an appropriate marker for measuring microvascular leakage in sputum. This "dual induction" model may used when testing the antiexudative effect of drugs. Chapter 5 demonstrated that the annual decline in FEV1 is related with CD8+ cells. This suggests that inflammatory phenotypes in asthma may have prognostic relevance. In chapter 6 is shown that PEF-variability provides information about asthma severity. Therefore, the current guidelines for the treatment of asthma can be improved by including PEF-variability. In chapter 7 is shown that anti-IgE improves PEF, diminishes allergen responses and is paralleled by a reduction in eosinophils in biopsies and sputum and a decline in IgE+ cells. This suggests that the clinical benefits of anti-IgE in asthma may be explained by a decrease in eosinophilic inflammation and IgE bearing cells. Show less