Tracking Macrophage Infiltration in a Mouse Model of Pancreatic Cancer with the Positron Emission Tomography Tracer [11C]PBR28

Abstract

<div class="section"> <a class="named-anchor" id="S1"> <!-- named anchor --> </a> <h5 class="section-title" id="d178605e163">Background:</h5> <p id="P2">The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) contains abundant immunosuppressive tumor associated macrophages (TAM). High level of infiltration is associated with poor outcome and is thought to represent a major roadblock to lymphocyte based immunotherapy. Efforts to block macrophage infiltration has been met with some success but non-invasive means to track TAMs in PDAC are lacking. Translocator protein (TSPO) is a mitochondrial membrane receptor which is upregulated in activated macrophages. We sought to identify if a radiotracer labeled cognate ligand could track macrophages in PDAC. </p> </div><div class="section"> <a class="named-anchor" id="S2"> <!-- named anchor --> </a> <h5 class="section-title" id="d178605e168">Materials and Methods:</h5> <p id="P3">A murine PDAC cell line was established from a transgenic mouse with pancreas specific mutations in KRAS and the p53. After confirming lack of endogenous TSPO expression, tumors were established in syngeneic mice. A radiolabeled TSPO specific ligand ([11C]PBR28) was delivered intravenously and tumor uptake assessed by autoradiography, ex vivo, or micro-PET imaging. </p> </div><div class="section"> <a class="named-anchor" id="S3"> <!-- named anchor --> </a> <h5 class="section-title" id="d178605e173">Results:</h5> <p id="P4">Resected tumors contained abundant macrophages as determined by immunohistochemistry and flow cytometry. Immunoblotting revealed murine macrophages expressed TSPO with increasing concentration on activation and polarization. Autoradiography of resected tumors confirmed [11C]PBR28 uptake and whole mount sections demonstrated the ability to localize tumors. To confirm the findings were macrophage specific, experiments were repeated in CD11b deficient mice and the radiotracer uptake was diminished. Micro-PET imaging validated radiotracer uptake and tumor localization in a clinically applicable manner. </p> </div><div class="section"> <a class="named-anchor" id="S4"> <!-- named anchor --> </a> <h5 class="section-title" id="d178605e178">Conclusion:</h5> <p id="P5">As new immunotherapeutics reshape the PDAC microenvironment, tools are needed to better measure and track immune cell subsets. We have demonstrated the potential to measure changes in macrophage infiltration in PDAC using [11C]PBR28. </p> </div>