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.

Keywords: cancer immunology; colorectal cancer; organ-on-a-chip (OOC); tissue engineering; tumor microenvironment.

Figure 1

(A) Colorectal liver metastasis models. Bolded applications are particularly well suited for the model. Even in the same category of model, constituent models can vary greatly, based on design, method, and study goals. (B, C) Colorectal cancer (CRC) “organ-on-a-chip” (OOC) platforms can model the immune response to tumors. (B) CRC cells (red) and IFN-DCs (green) are cultured in an OOC device (see cartoon) to simulate immune crosstalk. IFN-DCs migrate towards and phagocytose CRC cells following treatment with interferon-α and romidepsin. Images have been adapted from Parlato et al’s 2017 Scientific Reports article (38). (C) M1 and M2 macrophages (red) cultured with CRC cell lines (not shown) in a vascularized OOC platform (vessels shown in green) display anti- and pro-tumor effects, respectively. Figure was originally published in Bi et al’s 2020 Integrative Biology report (39).