Advances in Modeling the Immune Microenvironment of Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third most common cancer and second leading cause of cancer-related death in the US. CRC frequently metastasizes to the liver and these patients have a particularly poor prognosis. The infiltration of immune cells into CRC tumors and liver metastases accurately predicts disease progression and patient survival. Despite the evident influence of immune cells in the CRC tumor microenvironment (TME), efforts to identify immunotherapies for CRC patients have been limited. Here, we argue that preclinical model systems that recapitulate key features of the tumor microenvironment—including tumor, stromal, and immune cells; the extracellular matrix; and the vasculature—are crucial for studies of immunity in the CRC TME and the utility of immunotherapies for CRC patients. We briefly review the discoveries, advantages, and disadvantages of current in vitro and in vivo model systems, including 2D cell culture models, 3D culture systems, murine models, and organ-on-a-chip technologies.

Microfluidic technologies for immunotherapy studies on solid tumours

“…85 This is certainly the case where 2D, cost-effective cell monolayers are used. 30,86 In vitro 3D models using ex vivo human tumour tissues, 87 such as spheroids and organoids, 88 are increasingly being used, but the immunecomponent, vasculature and other stromal components of such models are often neglected. 89,90 The lack of in vitro models that adequately represent the native in vivo environment remains a significant hurdle in the preclinical development of immunotherapy.…”

“…29 The complexity originating from the intricate spatial cellular organizations within the TME and their interactions with immune inhibitory mechanisms highlights the need for complex in vitro models that faithfully mimic human in vivo scenarios. 30,31 Various solutions to these challenges can be provided by microfluidic and organ-on-achip technologies that enable miniaturisation, maximise the use of intact human tumour tissue, allow the robust and controlled modelling of tumour microenvironment characteristics and facilitate the culture of multiple cell types in defined spatial and temporal configurations. 27 The application of these technologies in the field of immuneoncology is discussed in more detail below.…”

Viscoelasticity, Like Forces, Plays a Role in Mechanotransduction

“…There are also organ-on-a-chip models that fully grasp the 3D microenvironment of cancer cells ( Glaser et al, 2022 ). For example, the immune microenvironment of cancer cells has been analyzed employing these organ-on-a-chip technologies ( Yoon et al, 2020 ). Long-term studies are possible without leading to an excess of cell death and less growth factors need to be supplemented.…”

Photodynamic Therapy-Mediated Immune Responses in Three-Dimensional Tumor Models

“…Two-dimensional (2D) cell culture models present several advantages such as cost-effectiveness and simplicity in terms of preparation, maintenance, and monitoring, allowing for amenable microscopic and molecular investigations [ 13 ]. However, 2D cultures rely on cells adhering to the host flat surface, normally a flask or plate, which does not mimic the 3D architecture of tumor tissues ( Figure 2 A) [ 14 ]. Furthermore, the cells are exposed to a relatively steady and uniform source of oxygen, nutrients, and growth factors, preventing them from resembling the in the vivo tumor microenvironment (TME) [ 13 , 14 ].…”

“…However, 2D cultures rely on cells adhering to the host flat surface, normally a flask or plate, which does not mimic the 3D architecture of tumor tissues ( Figure 2 A) [ 14 ]. Furthermore, the cells are exposed to a relatively steady and uniform source of oxygen, nutrients, and growth factors, preventing them from resembling the in the vivo tumor microenvironment (TME) [ 13 , 14 ]. For example, cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), endothelial cells (ECs), and cancer-associated adipose (CAA) are key components of breast cancer progression and carcinogenesis that compromise the tumor microenvironment [ 15 ].…”