Engineering an anti-CD206-synNotch receptor: insightsinto the development of novel synthetic receptors

Abstract

Immune cells play a pivotal role in the establishment, growth and progression of tumors at primary and metastatic sites. Macrophages, in particular, play a critical role in suppressing immune responses and promoting an anti-inflammatory environment through both direct and indirect cell-cell interactions. However, our understanding of the mechanisms underlying such interactions is limited due to a lack of reliable tools for studying transient interactions between cancer cells and macrophages within the tumor microenvironment. Recent advances in mammalian synthetic biology have introduced a wide range of synthetic receptors that have been used in diverse biosensing applications. One such synthetic receptor is the synNotch receptor, which can be tailored to sense specific ligands displayed on the surface of target cells. With this study, we aimed at developing a novel CD206-synNotch receptor, targeting CD206+ macrophages, a population of macrophages that play a crucial role in promoting metastatic seeding and persistent growth. Engineered in cancer cells and used in mouse metastasis models, such tool could help monitor and understand the effects cell-cell interactions between macrophages and cancer cells have on metastasis establishment. Here, we report the development of cancer landing pad cells for versatile applications, the engineering of CD206-synNotch cells, report the measurements of their activity and specificity, and discuss the unexpected caveats when considering their in vivo applications.