Abstract
Cancer is among the leading causes of global deaths. This is despite significant advances in cancer treatment and understanding where especially immunotherapy has shown promising results in recent years. Overall response rates are, however, still modest and have been correlated to composition and polarization of the infiltrating immune cells in the tumor microenvironment (TME). Here, infiltration of myeloid immune cells into the TME is typically associated with worse prognosis and treatment response while CD8+ T cells are generally positive for prognosis and treatment outcome. Despite primarily having a harmful role in cancer, myeloid cells can be repolarized using immune stimulatory compounds and thus become beneficial. The first manuscript in this dissertation provides comparative data of the TME across 11 murine subcutaneous cancer models with a focus on myeloid cells. Many of the investigated models are commonly used in preclinical evaluation and development of immunotherapies but prior to this work, comparative data has been lacking. The results demonstrated major differences in tumor-infiltrating myeloid cells across the evaluated cancer models. By providing comparative data across cancer models, the manuscript is valuable for explaining differences in treatment responses across cancer models and thereby presents a valuable tool for selecting relevant preclinical cancer models and helps to bridge the gap between preclinical research and clinical results. The second manuscript investigates the obstacles associated with delivery of innate immune stimulatory molecule in nanoparticles. The manuscript demonstrates that nanoparticles containing immune stimulatory molecules may be recognized by the immune system and subsequently be rapidly eliminated from blood circulation. This was accompanied by acute hypersensitivity symptoms and associated with IgG specific for the nanoparticles. The third enclosed manuscript describes preclinical evaluation for a nanoparticle containing an innate immune stimulatory compound developed within the group. The nanoparticle could be safely administered in preclinical animals and demonstrated potent anti-cancer effect and synergistic effect with other anti-cancer therapies in murine cancer models. Upon intravenous injection, cell viability within murine tumors was found drastically reduced while spleens were unaffected.
Info
Thesis PhD, 2019
UN SDG Classification
DK Main Research Area
Science/Technology
