Shortwave infrared emitting nanoprobes for imaging cancer immunosurveillance
Creators: name: Shah, Jay Vikram
Publisher: name: No Publisher Supplied
Year: 2023

description: Biomedical imaging plays a prominent role in cancer medicine, from aiding in diagnosing cancer to monitoring responses to systemic pharmacotherapies including an advancing array of immunotherapies. In recent years, checkpoint immunotherapy has revolutionized the field of oncology, given its potential to achieve remission and improved survival in patients with several cancer types by re-invigorating immune cells to elicit anti-tumor responses. However, many patients do not respond favorably or robustly to immune checkpoint inhibitors (ICIs), and current imaging techniques are unable to accurately stratify responders from non-responders. There remains a critical need to identify definitive biomarkers that can predict and monitor therapeutic responses to ICIs in order to provide optimal care to patients. Immune infiltration in the tumors may serve as a predictive determinant of immunotherapy outcomes, but there are currently limited options for non-invasive, real-time assessment of the immune burden, with the most common approaches involving “static” snapshots via immunohistochemical staining of tumor biopsy samples and radiation-based nuclear imaging. In contrast, optical imaging can provide a non-ionizing, non-invasive, and real-time approach to discern tumor-immune interactions, which forms the central premise for this dissertation research. This thesis is focused on exploring the design and application of molecularly targeted nanoprobes as optical imaging contrast agents to survey the immune landscape of the tumor microenvironment and elucidate possible links to consequent therapeutic responses. Specifically, this work harnessed biocompatible albumin nanocomposites encapsulating near infrared (NIR)-excitable (λ=980 nm) rare earth metal-doped nanoparticles that emit shortwave infrared (SWIR) light (λ=1000-1700 nm), allowing for deeper tissue imaging and greater signal-to-background ratios than traditional optical probes. These nanoprobes, termed rare earth albumin nanocomposites (ReANCs), were engineered to target the CD8 receptor of cytotoxic T cells in the tumor microenvironment. Increased T cell binding afforded by CD8-targeting allowed for non-invasive imaging of immune infiltration in murine mammary fat pad tumors and also discerned immunologically active (“hot”) and passive (“cold”) tumors. Furthermore, the ability to track therapeutic responses with SWIR imaging was demonstrated through the administration of tumor-targeted, theranostic ReANCs that delivered chemotherapeutics to tumors while SWIR emissions from the ReANCs served as a metric of therapeutic efficacy. There was a strong correlation between the therapy response measured through tumor regression and the associated SWIR signal from tumor-targeted nanoprobes. Changes in immune infiltration in response to combination chemotherapy and checkpoint immunotherapy were determined as a measure of SWIR fluorescence intensity by combining the CD8-targeting and therapy monitoring capabilities of ReANCs. Notably, the differences in SWIR imaging among different treatment groups correlated with immunohistochemistry staining in a preliminary study. Overall, the cumulative findings of this dissertation demonstrate the potential for the design and application of shortwave infrared-emitting nanocomposites for cancer immunosurveillance imaging while laying the groundwork for monitoring immunotherapy responses based on T cell infiltration as a prognosticatory factor.