Preclinical Fluorescence-Guided Imaging Leveraging Surrounding Sentinel Tumor Microenvironment Identifies High-Risk Premalignant Pancreatic Lesions

Abstract Purpose: With surgery being the only potential cure for pancreatic cancer, high-risk premalignant pancreatic lesions often go unnoticed by palpation or white light visualization, leading to recurrence. We asked whether near-infrared fluorescence imaging of tumor-associated inflammation could identify high-risk premalignant lesions, leveraging the tumor microenvironment (TME) as a sentinel of local disease and, thus, enhance surgery outcomes. Experimental Design: Fluorescence-guided surgery was performed on genetically engineered mice (Ptf1a-Cre; LSL-KrasG12D/+; Smad4flox/flox [KSC]) at discrete stages of disease progression, histologically confirmed high-risk, premalignant lesions in postnatal mice to locally advanced pancreatic tumors in adults, using the imaging agent V-1520, a translocator protein (TSPO) ligand. Age-matched wild-type littermates were used as controls, while Ptf1a-Cre; LSL-KrasG12D/+(KC) mice modeled pancreatitis and precursors of low penetrance. Localization of V-1520 and tumor-associated macrophages amongst the TME was detected by immunofluorescence imaging. Results: V-1520 exhibited robust accumulation in the pancreata of KSC mice from the early postnatal stage. Increased accumulation was observed in the pancreata of adolescent- and adult-aged mice with greater ductal lesion and stromal burden. Confocal microscopy of ex vivo pancreas specimens co-localized V-1520 accumulation primarily with CD68-expressing macrophage in KSC mice. Unlike the pancreata of KSC mice, accumulation of V-1520 did not exceed background levels in the pancreata of KC mice with pancreatitis. Conclusion: V-1520 exhibited differential accumulation in pancreatic cancer-associated inflammation compared to pancreatitis. Given the robust tracer uptake in tissues associated with early yet high-risk lesions, we envision V-1520 could enhance surgical resection and reduce the potential for recurrence from residual disease.