Weizman et al. introduced an innovative synthetic notch-based system called TIINDRR (Tumor–Immune Interactome Non-biased Discovery Retroviral Reporter) designed to capture interactions between tumor and immune cells. Tumor cell “senders” express membrane-bound GFP (mGFP), which are recognized by immune cell “receivers” expressing an anti-GFP SynNotch receptor, inducing BFP to identify and record immune–tumor interactions within the tumor and in circulation. TIINDRR successfully documented unique interactomes using distinct immunogenic tumor subtypes and following cancer immunotherapies (anti-PD-1 or decoy-resistant IL-18).
Contributed by Shishir Pant
ABSTRACT: The ability of immune cells to directly interact with transformed cells is an essential component of immune surveillance and critical for optimal tissue function. The tumor-immune interactome (the collective cellular interactions between oncogenic cells and immune cells) is distinct and varied based on the tissue location and immunogenicity of tumor subtypes. However, comprehensive landscape and the consequences of tumor-interacting immune cells in the tumor microenvironment are not well understood. Current tools are limited in their ability to identify and record interactors in vivo or be utilized for downstream analysis. Here, we describe the development and validation of a technology leveraging synthetic Notch receptors reporting physical tumor cell-immune cell contact in vivo in order to decipher the tumor-immune interactome. We call this approach, Tumor-Immune Interactome Non-biased Discovery Retroviral Reporter or TIINDRR. Using TIINDRR, we identify the tumor-immune interactomes that define immunological refractory and sensitive tumors and how different immunotherapies alter these interactions. Thus, TIINDRR provides a flexible and versatile tool for studying in-vivo tumor-immune cell interactions, aiding in the identification of biologically relevant information needed for the rational design of immune-based therapies.