Every day, individuals receive a dreaded medical diagnosis – that they have cancer. Cancer continues to be a scary and sometimes devastating disease because much remains unknown about how cancers progress. However, one thing that has become clear is that cancer cells have developed complex ways to hijack our immune cells, reprogramming our cells to work in their favor. This allows the cancer cells to hide and multiply, rather than be eliminated. This phenomenon impacts how we treat cancers as well as how aggressive some cancers become. Anne Mette H. Larsen and her colleagues at Copenhagen University Hospital, Roskilde University, and the University of Southern Denmark, were interested in adding another piece to this puzzle. In an article published this summer in the Journal of Immunology, Larsen et al. demonstrated that a specific component of the cancer environment, collagen, can drive our immune cells to suppress their responses. This research has significant implications for why certain cancer therapies fail and why certain cancers have poorer outcomes than others.

Understanding the immune system and role of collagen

Collagen is one of the most abundant proteins in our body and wears many hats. Collagen can provide a scaffold on which our cells can grow, promote healing when we get a wound, and send signals to the cells in our body to grow, multiply, and develop. Importantly for these researchers, collagen has also been shown to send messages to our immune cells. When we have a breach in our protective barriers, introducing foreign invaders, our immune cells come prepared for battle. A specific type of immune cell called the macrophage is one of the first responders. Macrophages which reside in our tissues provide early, blanket responses to keep invaders at bay; however, these cells can’t eliminate the invaders on their own. Macrophages recruit additional help from specially trained immune cells that are better equipped to provide targeted responses and successfully clear infections. These include an immune cell type called the T cell. Once immune cells such as the T cell do their job, the tissues of our body can start to heal. Our macrophages must switch from helping fight battles to helping repair our tissues. Collagen helps communicate to macrophages that they need to change gears and halt their attack, no longer needing to recruit additional forces.

This system works well when we have an infection from a bacterium or virus but becomes faulty when cancer cells are introduced into the mix. Our macrophages are not trained to attack our own cells! Cancer cells exploit this loophole, making sure that macrophages within their environment assist the cancer in growing and hiding from any immune attacks. Larsen et al. explored one idea as to how cancer cells may effectively alter macrophage responses. Cancer cells, as they multiply and morph into solid tissue masses, have been shown to break down normal components of our tissue structure. These structures are replaced with increased amounts of densely packed, stiff collagen. As collagen normally switches macrophages away from attack mode, these researchers thought that increased amounts of collagen may shift the balance of messages received by macrophages so that they do not attack cancer cells. Our macrophages would no longer be first responders for battle! 

Investigating the impact of collagen density on macrophage function

To investigate this question, Larsen et al. grew macrophages within a 3-D model system, more closely mimicking the environment encountered within the body as compared to typical 2-D cell culture models. Within this system, cells were grown with either a high amount or a low amount of collagen. Interestingly, macrophages grown within the high-collagen environment expressed different amounts of genes related to their immune response when compared to cells grown within low-collagen environments. When digging deeper into the role those genes play, this research team identified an altered profile of genes used to make a specific class of molecules called chemokines. Chemokines work to attract other immune cells in the same way that the smell of a pie in the oven draws you from a different area of your house to your kitchen.

While this difference in gene expression was exciting, this research team wanted to take their experiments one step further and determine if the change in gene expression resulted in actual changes in the way these macrophages functioned. They wanted to see if their macrophages would be able to attract and support the growth of different immune cells that are important in fighting diseases. Interestingly, macrophages that were grown in high collagen environments were less efficient at recruiting a critical cell type that can kill invaders, called the cytotoxic T cell, and were more efficient at recruiting a cell type that is suppressive in their immune function, called the regulatory T cell. Cytotoxic T cells are known to be important in our immune responses against cancers, and regulatory T cells play a role in reducing inappropriate immune responses. The macrophages grown in high amounts of collagen also prevented the cytotoxic T cells from multiplying. If collagen is having this effect within the body of a person who has cancer, this means that their macrophages, whose job is normally to help fight off dangers and help recruit cytotoxic T cells, are contributing to the cancer cell’s ability to hide undetected from our immune system. This allows those cancer cells to grow and morph into the tumors that are so detrimental to our health. 

The importance of studying collagen’s role in cancer immunity

Larsen et al. were the first to demonstrate that a higher density of collagen causes macrophages to put on an immune suppressive mask. However, how collagen sends these signals to the macrophages to make them behave in this way is a question still to be answered. Additionally, these experiments were conducted within the laboratory setting, and more work is needed to see if this same finding applies to cancers in human patients. A better understanding of the interaction between collagen and macrophages within the cancer environment will help scientists develop better therapies to target cancer, help us understand why some treatments fail, and help us improve treatments already available. 

Journal Article: Anne Mette H. Larsen et al. “Collagen Density Modulates the Immunosuppressive Functions of Macrophages.” The Journal of Immunology September 1, 2020, 205 (5) 1461-1472; DOI: 10.4049/jimmunol.1900789

Cover Image: Cancer cell, CC BY