Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.
Department of Ophthalmology, Yale University School of Medicine, New Haven, CT 06520.
Proc Natl Acad Sci U S A. 2023 Oct 31;120(44):e2306632120. doi: 10.1073/pnas.2306632120. Epub 2023 Oct 23.
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.
免疫细胞直接与转化细胞相互作用的能力是免疫监视的重要组成部分，对于组织的最佳功能至关重要。肿瘤免疫相互作用组（致癌细胞和免疫细胞之间的集体细胞相互作用）因组织位置和肿瘤亚型的免疫原性而异。然而，肿瘤微环境中肿瘤相互作用的免疫细胞的全面情况及其后果尚不清楚。目前的工具在识别和记录体内相互作用因子的能力或用于下游分析方面存在局限性。在这里，我们描述了一种利用合成 Notch 受体在体内报告实体瘤细胞-免疫细胞物理接触的技术的开发和验证，以破译肿瘤免疫相互作用组。我们将这种方法称为肿瘤-免疫相互作用组无偏发现逆转录病毒报告基因或 TIINDRR。使用 TIINDRR，我们确定了定义免疫难治性和敏感性肿瘤的肿瘤免疫相互作用组，以及不同免疫疗法如何改变这些相互作用。因此，TIINDRR 为研究体内肿瘤-免疫细胞相互作用提供了一种灵活多样的工具，有助于识别基于免疫的治疗的合理设计所需的生物学相关信息。
