Engineered immune cells as highly sensitive cancer diagnostics

Abstract

Endogenous biomarkers remain at the forefront of early disease detection efforts, but many lack the sensitivities and specificities necessary to influence disease management. Inspired by emerging adoptive cell transfer immunotherapies and the natural migration of immune cells to pathology, here we describe a new class of cell-based in vivo sensors for ultrasensitive disease detection. In our proof of concept, we perform adoptive transfer of syngeneic macrophages which were engineered to produce a synthetic biomarker upon adopting a 'tumor-associated' metabolic profile. Notably, the macrophage sensor detected tumors as small as 25-50 mm 3 , effectively tracked the immunological response in two models of acute inflammation, and was more sensitive than both protein and nucleic acid cancer biomarkers. This technology establishes a clinically translatable approach to early cancer detection and provides a conceptual framework for the use of engineered immune cells for the monitoring of many disease states in addition to cancer.

Macrophages and the maintenance of homeostasis

“…One of the major challenges in treating cancer is the detection of early metastasis. Gulati and colleagues 18 recently developed an engineered macrophage reporter that expresses luciferase under the control of the arginase-1 promoter. Thus, when this cell is attracted to the tumor microenvironment, it becomes a macrophage with a tumor-associated profile (tumor-associated macrophage) and begins to express luciferase, which can be easily detected to indicate possible metastasis.…”

“…Thus, when this cell is attracted to the tumor microenvironment, it becomes a macrophage with a tumor-associated profile (tumor-associated macrophage) and begins to express luciferase, which can be easily detected to indicate possible metastasis. 18 As we have come to better understand the transducer functions of macrophages, we have realized that the simple M1/M2 classification of macrophages simply does not reflect reality, and that these cells can be manipulated in predictable ways simply by changing the input stimuli.…”

Ultra-small bimetallic iron–palladium (FePd) nanoparticle loaded macrophages for targeted tumor photothermal therapy in NIR-II biowindows and magnetic resonance imaging

“…Macrophages have been proven as an excellent nanoparticles carrier with small side effects and good tumor targeting. [29][30][31][32] FePd NPs loaded macrophages (FePd@M) can be targeted to the tumor site, which also greatly increased the accumulation of nanoparticles in the tumor site. Compared with the control group and exposed nanoparticles, FePd@M showed a stronger photothermal treatment effect (about 90% of tumors are ablated) and better nuclear magnetic imaging.…”

Building sophisticated sensors of extracellular cues that enable mammalian cells to work as “doctors” in the body

“…Further, expanding the repertoire of output from proteins to other modalities would be also useful. For example, we reported implantable mammalian cells capable of secreting designer exosomes that can efficiently deliver encapsulated therapeutic mRNA into target cells [66]. By combining this kind of system to deliver functional nucleic acids and the sensor systems described in this review, it should be possible to construct on-demand RNA delivery systems.…”