Finding that M2 macrophages form a major immune subset within solid tumors, Aalipour et al. engineered macrophages expressing secreted Gaussia luciferase (Gluc) downstream of the arginase-1 promoter as a cancer diagnostic. Bone marrow-derived and RAW264.7 macrophages migrated and upregulated Arg1 in response to tumor-conditioned media in vitro, and co-localized with tumors in vivo. Plasma Gluc from transferred macrophages detected metastases and subcutaneous tumors as small as 25mm3 with higher sensitivity than shed-tumor-antigen and cell-free DNA biosensors, and tracked wound healing in models of inflammation.
Contributed by Alex Najibi
Endogenous biomarkers remain at the forefront of early disease detection efforts, but many lack the sensitivities and specificities necessary to influence disease management. Here, we describe a cell-based in vivo sensor for highly sensitive early cancer detection. We engineer macrophages to produce a synthetic reporter on adopting an M2 tumor-associated metabolic profile by coupling luciferase expression to activation of the arginase-1 promoter. After adoptive transfer in colorectal and breast mouse tumor models, the engineered macrophages migrated to the tumors and activated arginase-1 so that they could be detected by bioluminescence imaging and luciferase measured in the blood. The macrophage sensor detected tumors as small as 25-50 mm(3) by blood luciferase measurements, even in the presence of concomitant inflammation, and was more sensitive than clinically used protein and nucleic acid cancer biomarkers. Macrophage sensors also effectively tracked the immunological response in muscle and lung models of inflammation, suggesting the potential utility of this approach in disease states other than cancer.
Author Info: (1) Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford
Author Info: (1) Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. (2) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. (4) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (5) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA. (7) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA. (8) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (9) Division of Blood and Marrow Transplantation, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. (10) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. (13) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (14) Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Bioengineering, Stanford University School of Medicine, Stanford, CA, USA. sgambhir@stanford.edu. Molecular Imaging Program at Stanford, Stanford University School of Medicine, Stanford, CA, USA. sgambhir@stanford.edu. Department of Radiology, Stanford University School of Medicine, Stanford, CA, USA. sgambhir@stanford.edu. Canary Center at Stanford for Cancer Early Detection, Stanford University School of Medicine, Palo Alto, CA, USA. sgambhir@stanford.edu. Department of Materials Science and Engineering, Stanford University, Stanford, CA, USA. sgambhir@stanford.edu.
