Globally, breast cancer has the highest rates of incidence and mortality among women. For breast cancer diagnoses, while there is a 99% five-year relative survival rate for localized disease, survival drops to 29% for progression to metastatic disease. And, although robust advances have been made in the treatment of localized breast cancer, few therapies exist to effectively treat metastases. As such, distant spread marks the disease stage where treatment no longer has curative intent, and disease progression leads to mortality. The increased mortality with metastasis motivates the development of diagnostic and therapeutic strategies for managing metastatic disease, and I hypothesize that the microenvironment at the metastatic niche can serve as a target for these strategies.

First, I present a study investigating the utility of cargo-free PLGA nanoparticles (NPs) that, upon intravenous delivery, can be internalized by myeloid cells and subsequently alter their impact on the metastatic niche. We demonstrated that NPs reduce metastatic colonization of the lungs in a murine model of metastatic triple negative breast cancer (mTNBC). The NPs were found to modulate the immune microenvironment of the lungs, skewing myeloid cells toward inflammatory, anti-tumor phenotypes through single cell RNA sequencing. We then found that the reduction of metastatic spread was dependent on mature T-cells. Finally, NPs were administered in a primary tumor (PT) resection model and shown to lead to clearance of established metastatic lesions when delivered as an adjuvant therapy, following surgical resection.

The treatment of TNBC with immune checkpoint blockade (ICB) therapy, a T-cell targeted immunotherapy, has shown robust improvements in patient outcomes. However, while ICB-sensitive patients have durable responses to therapy, no effective biomarkers are available for predicting ICB-response and stratifying ICB-sensitivity from ICB-resistance. Our lab has previously shown that the immune milieu of a microporous PCL implant, which recapitulates key features of the native metastatic niche, can be longitudinally probed for monitoring 1) progression of cancer and 2) response to a PT resection. I investigate the hypothesis that the microporous implant can be longitudinally probed for ICB-response. Divergent responses in TNBC progression, as a result of anti-PD-1 administration, were identified and gene expression at the implant allowed for the ability to monitor ICB-response. Differential lymphocyte and myeloid cell responses were also identified that are correlative of the divergent responses to therapy. Finally, implant-derived gene expressions were probed prior to treatment to investigate predictive analytes for ICB-response before initiating therapy.

Overall, this dissertation demonstrates the potential for applying engineered materials to 1) modulate cancer-associated myeloid cells to enhance anti-tumor T-cell surveillance with the goal of clearing metastatic disease and 2) probe biomarkers to stratify ICB-response and investigate mechanisms underlying therapy resistance.

Date: Wednesday, April 6, 2022
Time: 2:00 PM EST
Zoom: https://umich.zoom.us/j/94478502873
Chair: Professor Lonnie D. Shea