Despite the improvements made in the treatment of cancer in the last 50 years, metastasis still results in up to 90% of cancer related deaths. Metastatic tumor cells are not only more aggressive but they are often less immunogenic, able to escape detection and elimination by the immune system. In addition, tumor-secreted factors induce the proliferation and activation of aberrant immune cells that further suppress the anti-tumor immune response. New findings in the fields of cancer biology and cancer immunology have enabled the development of targeted therapies and immunotherapies that act to reverse this immunosuppression. The work presented here aims take an engineering approach to build upon these findings. The development and application of biomaterial platforms that can interact with and modulate immune cells, may enable better understanding and treatment of underlying mechanisms driving cancer progression and metastasis.
This work describes the application of biomaterial nanoparticles as a novel treatment for acute inflammation resulting from spinal cord injury. The nanoparticles were internalized by proinflammatory immune cells, and diverted these cells away from the injury site while reprogramming macrophages at the site to be more pro-regenerative. Increased tissue regeneration, reduced scarring, and improved functional recovery of the animal were observed with nanoparticle treatment. The immunomodulatory capabilities of nanoparticles were also tested in a model of metastatic breast cancer. The nanoparticles were found to be internalized by disease-relevant immune cells and reduced the abundance of these cells in circulation as well as at the metastatic site. The immunomodulation resulted in slower tumor growth, fewer metastatic cells at the lung, and a survival benefit when combined with anti-PD-1 therapy. This work also explores the use of implantable biomaterial scaffolds for monitoring metastasis and disease progression, and introduces a scoring metric based on gene expression of cells recruited to the scaffold to predict therapeutic outcome and the likelihood of relapse. The scaffolds were also utilized to study the dynamics of Gr1$+ cell phenotype at sites of metastasis. RNA sequencing and functional studies revealed differences in the phenotype of these cells across tissues and over time. These studies add to the existing body of knowledge of Gr1+ cells and introduces potential considerations in the development of drugs targeting these cells.PHDChemical EngineeringUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/163265/1/zyining_1.pd
