Physical Immunoevasion: Attenuated Mechanical Communication Facilitates Metastatic Colorectal Cancer Cells to Evade Macrophage Attack

Background Introduction

Cancer metastasis is a complex and daunting challenge, with metastatic cancer cells capable of evading immune cell attacks, breaching the extracellular matrix (ECM), and migrating to other sites to establish secondary tumors. While the importance of biochemical signals in the tumor immune microenvironment affecting cancer cell immune evasion and metastasis is well established, the role of physical factors in the environment remains underexplored. Specifically, the role of ECM-mediated mechanical interactions between cancer cells and immune cells in cancer cell immune evasion is still unclear. Recent studies have shown that mechanical signals in the microenvironment are crucial in regulating biological processes and have garnered interest in immune activities.

Source of Paper

This research article was authored by Chen Yang and colleagues from Beihang University, Beijing Institute of Physics, Chinese Academy of Sciences, and other institutions. The paper was published in the Proceedings of the National Academy of Sciences (PNAS) on May 21, 2024, titled “Physical Immunoevasion: Attenuated Mechanical Communication Facilitates Metastatic Colorectal Cancer Cells to Evade Macrophage Attack.”

Research Process and Methods

To explore the role of mechanical signals in the interactions between cancer cells and immune cells, researchers constructed an in vitro quasi three-dimensional co-culture system, using Type I collagen hydrogels to mimic the ECM background of the in vivo environment, and studied the responses of two colorectal cancer cell lines with different metastatic potentials (SW480 and SW620) to macrophages.

Research Steps

a) Research Objects and Experimental Process: In this study, SW480 and SW620 cells were first co-cultured with PMA-treated macrophages (U937) using collagen gels to provide mechanical support and signals. The cells were co-cultured at a 1:25 ratio on top of 2 mg/ml collagen gels. To measure these responses, particle image velocimetry (PIV) was used to measure ECM deformation induced by cancer cell traction forces, and micropipettes controlled by micromanipulators were employed to simulate the traction forces of the two types of cancer cells on the ECM.

b) ECM Deformation Analysis and Macrophage Response: By separately culturing SW480 and SW620 cells on 2 mg/ml collagen gels with fluorescent beads, deformation results were analyzed using PIV. SW480 cells generated extensive deformation within 12 hours through their traction forces, while SW620 cells produced minimal mechanical signals within the same timeframe.

Experimental Results and Data Analysis

b) Experimental Results and Logical Relationships: The results indicated that the traction forces of SW480 cells caused significant deformation of the ECM, enabling macrophages to effectively recognize and attack SW480 cells through mechanical signals. However, highly metastatic SW620 cells exhibited weak traction forces and deformation, making it difficult for macrophages to recognize and attack them, thereby achieving immune evasion. In control group experiments, macrophages and cancer cells were co-cultured on solid culture dishes without ECM, and the targeting rate of macrophages for both SW480 and SW620 cells was below 5%. Increasing ECM stiffness also reduced the targeting attraction rate of macrophages to SW480 cells.

c) Conclusion and Research Significance: This indicates that the different ECM deformations between SW480 and SW620 cells and the macrophages’ response to these deformations demonstrate that the ECM, through tension signal transduction, plays an important role in determining the targeting efficiency of macrophages and the immune evasion capability of cancer cells. Low-metastatic potential SW480 cells induce strong ECM remodeling and deformation through ECM, enabling macrophages to sense their mechanical signals and target them. Highly metastatic SW620 cells, due to weakened mechanical contraction on the ECM, are able to evade macrophage attack. Further, the study used small interfering RNA (siRNA) to reduce the expression of E-cadherin in SW480 cells, weakening their traction force, which again confirmed the key role of mechanical communication in cancer cell immune evasion.

Important Findings and Highlights

• Special Findings: The study systematically demonstrated for the first time the mechanical behavior of colorectal cancer cells with different metastatic potentials on the ECM and their effects on macrophage responses.
• Key Points: Mechanical deformation and communication of the ECM play a crucial role in immune evasion and cancer cell recognition.
• Novelty of the Study: The use of a quasi three-dimensional co-culture system, combined with advanced experimental methods such as PIV technology and micro-manipulated mechanical loading, revealed the role of mechanical signals in the tumor immune microenvironment.

Research Value

By revealing the role of mechanical signals in the interactions between cancer cells and immune cells, this study provides a key reference for further in-depth research on cancer immunotherapy strategies. Understanding how macrophages target and clear cancer cells through mechanical signals can lay the foundation for developing new anti-cancer therapies in the future. This discovery not only enriches our understanding of tumor immune evasion but also provides new ideas for exploring new treatment methods.

Conclusion

By constructing an in vitro quasi three-dimensional co-culture system, this study reveals for the first time the differences in mechanical signals of colorectal cancer cells with different metastatic potentials on the ECM and their response mechanisms to macrophages. This finding provides a new perspective for future cancer immunotherapy strategies, promising positive impacts on in vitro experiments and clinical applications.