Date of Award

Spring 5-1-2025

Document Type

Thesis (Ph.D.)

Department or Program

Cancer Biology

First Advisor

Kimberley S. Samkoe

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the cancer treatment landscape, yet their clinical efficacy remains limited to a subset of patients. Existing biomarkers used to select patients for ICIs are imperfect predictors of therapeutic response and offer static snapshots of highly dynamic tumor-immune interactions. To address this limitation, this thesis develops and validates a novel technique – multi- spectral paired-agent imaging of receptors (mPAIR) – to quantify immune checkpoint proteins in vivo. Focusing on the PDL1 axis, this work integrates receptor-binding studies, molecular imaging, and optical engineering to develop a multiplexed in vivo imaging technique. First, a panel of targeted imaging agents and near-infrared fluorophores was systematically selected and optimized for mPAIR. Liquid and tumor-mimicking phantoms were used to validate fluorophore spectral distinction and diffusion dynamics, confirming multi-target quantification of PDL1, PD1, and CD80. In an in vivo syngeneic murine lymphoma model, receptor concentrations of PDL1, PD1, and CD80 calculated from mPAIR strongly correlated with quantitative flow cytometry-derived receptor counts, despite challenges associated with bound residual imaging agents. Collectively, these findings establish mPAIR as a promising tool for quantitative and real-time profiling of immune checkpoint availability in tumor models. Overall, this work lays the foundation for utilizing optical imaging biomarkers to improve patient selection and therapeutic monitoring for ICI therapies.

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