Synthetic biology approach to monitoring transient interactions between cancer and immune cells

Abstract

Immune cells play an important role in tumour growth and progression, as well as establishment at metastatic sites. Although inherently, immune system is designed to locate, target and eliminate malignant cells, evolutionary processes within a host allow tumourigenic cells to develop mechanisms and pathways to avoid immune recognition. There is a substantial amount of knowledge on how particular immune cell subtypes contribute to cancer growth and progression.

Specifically, macrophages play an important role in mitigating immune response and induction of anti-inflammatory response. Due to this reason, macrophages can become potential new therapeutic targets. However, the knowledge of underlying mechanisms is limited due to the absence of robust tools for studying transient cell-cell interactions between cancer cells and macrophages at tumour microenvironment. Recent advances in synthetic biology have introduced a vast array of tools, particularly synthetic receptors, which have reported a broad range of applications in biosensing. One of such tools is synNotch receptor, which is derived from the core of the Notch receptor and is activated by cell-cell contact.

Both extracellular and intracellular domains of synNotch can be substituted with custom sensing and signal transduction domains to carry out custom input/output circuits. In this thesis, the aim is to repurpose synNotch to detect interactions between cancer cells and macrophages in aims to develop a robust tool to aid in studying the mechanisms of metastasis development and bring insights into potential therapeutic targets.