Immunotherapeutic and Diagnostic Potential of Engineered Materials

Abstract

Globally breast cancer has the highest rates of incidence and mortality among women, and the progression of localized breast cancer to metastatic disease is associated with a stark decrease in survival. Although robust advances have been made in the treatment of localized disease, few effective therapies exist to treat metastasis. As such, distant spread marks the disease stage where treatment no longer has curative intent, and disease progression leads to mortality. Decreased survival, as a result of metastatic progression, emphasizes the necessity for developing diagnostic and therapeutic strategies to manage metastatic disease, and I hypothesize that the microenvironment of the metastatic niche can serve as a target for these strategies. In Chapter 2 and Chapter 3 I present studies investigating the utility of cargo-free PLG nanoparticles (NPs) that, upon intravenous delivery, can be internalized by myeloid cells, altering their impact on an anti-tumor immune response at 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 reduced metastatic spread was dependent on mature T-cells. Finally, NPs were administered in a primary tumor (PT) resection model and shown to clear established metastatic lesions when delivered as an adjuvant therapy, following surgical resection. Immunomodulatory therapies have become an integral component of cancer management, along with surgery, chemotherapy, and radiation therapy. Furthermore, the treatment of TNBC with immune checkpoint blockade (ICB) therapy, a T-cell-targeting immunotherapy, has shown robust improvements in patient outcomes. However, while ICB-sensitive patients experience durable responses to therapy, there are no effective biomarkers available to predict ICB-response or stratify ICB-sensitivity from resistance. Our lab has previously investigated the utility of a microporous PCL scaffold that integrates with the host upon surgical implantation, finding that the immune milieu of the implant recapitulates key features of the native metastatic niche. We have shown that gene expressions from the implant microenvironment can be longitudinally probed to monitor 1) progression of cancer and 2) response to a PT resection. As such, in Chapter 4, I investigate the hypothesis that the microporous implant can be longitudinally probed to glean insight into ICB-response. Divergent responses to therapy were observed when treating murine TNBC with anti-PD-1, and gene expressions at the implant were probed to monitor ICB-sensitivity versus resistance. Differential lymphocyte and myeloid cell responses were identified for the divergent therapy responses. Finally, implant-derived gene expressions were probed before ICB administration, illuminating predictive analytes for ICB-response prior to initiating therapy. Overall this dissertation demonstrates the potential for applying engineered materials to 1) treat metastatic disease by modulating cancer-associated myeloid cells with the goal of enhancing anti-tumor T-cell surveillance and 2) stratify divergent ICB-responses and investigate mechanisms underlying therapy sensitivity versus resistance.