Exploring Tumor-Immune Interactions in Co-Culture Models of T Cells and Tumor Organoids Derived from Patients

Abstract

The use of patient-derived tumor tissues and cells has led to significant advances in personalized cancer therapy and precision medicine. The advent of genomic sequencing technologies has enabled the comprehensive analysis of tumor characteristics. The three-dimensional tumor organoids derived from self-organizing cancer stem cells are valuable ex vivo models that faithfully replicate the structure, unique features, and genetic characteristics of tumors. These tumor organoids have emerged as innovative tools that are extensively employed in drug testing, genome editing, and transplantation to guide personalized therapy in clinical settings. However, a major limitation of this emerging technology is the absence of a tumor microenvironment that includes immune and stromal cells. The therapeutic efficacy of immune checkpoint inhibitors has underscored the importance of immune cells, particularly cytotoxic T cells that infiltrate the vicinity of tumors, in patient prognosis. To address this limitation, co-culture techniques combining tumor organoids and T cells have been developed, offering diverse avenues for studying individualized drug responsiveness. By integrating cellular components of the tumor microenvironment, including T cells, into tumor organoid cultures, immuno-oncology has embraced this technology, which is rapidly advancing. Recent progress in co-culture models of tumor organoids has allowed for a better understanding of the advantages and limitations of this novel model, thereby exploring its full potential. This review focuses on the current applications of organoid-T cell co-culture models in cancer research and highlights the remaining challenges that need to be addressed for its broader implementation in anti-cancer therapy.

Keywords: T cells; co-culture system; patient-derived organoid; tumor microenvironment.

Figure 1

Various types of 2D and 3D in Vitro Cell Culture Models. The classical co-culture platform involves embedding 2D cancer cell lines and immune cells into a cell culture dish. Media can be transferred to another dish for this purpose. In the transwell co-culture system, immune cells are embedded in a matrix on top of a transwell insert, while cancer cells are embedded in the bottom. A 3D spheroid co-cultured with immune cells represents a 3D cell culture model where cells aggregate to form a spherical structure. The integration of organoids, immune cells, and cancer-associated fibroblasts (CAFs) is achieved by embedding them in Matrigel. Microfluidic chambers, also referred to as organ chips, are miniature devices designed to mimic the functions of human organs on a microscale. These chips are typically constructed from transparent materials like silicone or glass and feature tiny channels or chambers that can be lined with human cells. The primary component of these microfluidic chambers is the irrigation-controlled microchannel, which supports the growth of various living cells such as cell lines, immune cells, and organoid endothelial cells.

Figure 2

Schematic diagram of patient-derived 3D organoid–T cell co-culture models and application. Tumor tissues are collected after surgical resections to isolate TILs and generate organoids from patients. Additionally, autologous PBMCs can be isolated from the blood. The co-culture model of organoids and T cells is optimized for studying disease modeling, patient-specific drug responsiveness, and signaling pathways mediated by interactions in the TME, representing biological relevance. It can be applied in various research areas.