How The Immune System Can Promote Metastasis

BY Dr. Agnieszka Swierczak, Ph.D.


The immune system is a multifaceted network made up of numerous factors, cell types, and signaling pathways that are all interconnected and often redundant; in this case meaning that if one pathway fails there are others that can be activated to maintain the same function. This set up is highly specialized, highly organized and extremely effective, allowing our immune system to efficiently react to, and protect us from invading pathogens, such as bacteria and viruses. So much so, that most of the time we are not even aware our immune system has fought off an infection. However, this is not always the case when it comes to cancer. Although it was originally believed that the immune system was in fact attempting to attack and eliminate tumors, and that these attacks were unsuccessful, recent data has shown that tumors actually capitalize on the normal functions of the immune system to promote their own growth and progression. Before we delve further into this concept, it is important that we understand some of the intricacies of the immune system. The immune system is made up two arms, the innate immune system which constitutes the first line of defense and the adaptive immune system, which is more specialized and enlisted during the later stages of immune responses. The innate immune system is first to encounter and identify any invading bacteria or virus, or any type of injury. One of the key types of innate immune cells are macrophages.  Macrophages are also known as big eaters, coming from the Greek translation makros “large” and phagein “eat.” They are so called because they are constantly “sampling” the surrounding environment by continuously ingesting particles to identify anything that would not normally be there, including bacteria or viruses, and pieces of tissue released due to damage. Macrophages are highly complex and can execute a vast number of functions during immune responses. They are also highly flexible, meaning they can easily change what functions they are carrying out as required, the scientific name for this is phenotypic plasticity.

For the sake of simplicity let us separate the macrophages into two main types, although in reality due to their plasticity there is large range of macrophage phenotypes. The first type of macrophages are called activated macrophages, or M1-like macrophages. As soon as these activated macrophages detect something is wrong in the body they basically go ballistic. They destroy everything in sight, they don’t discriminate between self (normal tissue)  and non-self (the invading bacteria or viruses) their goal is to kill the invaders by whatever means necessary, regardless of what else they demolish in the process. However, this process cannot continue unchecked as eventually excessive damage to the normal tissue will result in serious side effects. This brings me to the second type of macrophage, the alternatively activated, or M2-like, macrophages. These macrophages calm the activated macrophages down. They soothe them, talk to them, listen to their problems, give them a nice cup of tea and send them off, back to patrolling the perimeters. The alternatively activated macrophages then rebuild. They patch up ruined tissues, build new tissues, reconstruct supply lines, restore broken blood vessels, and create new blood vessels. All of this restores normal function in that area of the body. They key thing that needs to be understood about macrophages is that any macrophage, at any given time, can switch from an activated macrophage into an alternatively activated macrophage or vice versa.

Tumors are also highly complex; they are made up of many different cell types including tumor cells, the supporting tissue cells (which are called stromal cells), and of course immune cells. As with the immune system, there exists a complex network of signaling pathways within the tumors that involves a myriad of factors; in the scientific world this is called the tumor microenvironment. Tumor cells themselves are not capable of carrying out many of the functions they require for growth and progression. In fact, they mostly rely on the normal cells within the tumor microenvironment to do things for them. It has been very well established, through decades of research, that the macrophages are one of the key cell types that the tumor cells take advantage of. Although the interactions between macrophages and tumors are highly complex, and often confusing, we do know that the tumors send out signals resembling those that normal wounded tissues would, leading to the recruitment of macrophages. Furthermore, the tumors then manipulate the recruited macrophages to carry out functions normally executed by the alternatively activated macrophages and not activated macrophages.  Macrophages that are recruited into tumors, and that are phenotypically similar to alternatively activated macrophages are called tumor-associated macrophages, or TAMs. There is a theory in the scientific world that TAMs see the tumor as a wound, and are simply trying to heal it; hence we often refer to tumors as “wounds that do not heal.” The problem with this is that the functions of TAMs actually help the tumor grow and progress. There are a number of different ways this can happen.

In order for a tumor to grow and progress it needs to establish supply lines to get sufficient amounts of nutrients and oxygen. Without these supply lines the tumors cannot grow beyond 2-3 mm2 in size. These supply lines come in the form of blood vessels and since tumors cannot actually grow these blood vessels themselves, they trick the TAMs into doing it for them. Angiogenesis is the process of new blood vessel development and TAMs secrete a number of factors that promote angiogenesis, which in turn provides tumors with all the oxygen and nutrients they need. Alternatively activated macrophages also secrete a large number of growth factors. These factors stimulate the growth of a number of different cell types which is required for successful tissue repair and angiogenesis. Tumor cells also respond to growth factors and by stimulating TAMs to secrete these factors tumors can maintain their own cellular growth. Another example of how tumors trick TAMs into supporting their own growth and progression is by getting them to suppress the adaptive immune system. Earlier, I mentioned that there are two arms within the immune system, the adaptive and the innate. The adaptive immune system is more specialized than the innate immune system. Adaptive immune cells are like commandos or special ops, highly specialized units that kill only the intended target. In order to survive tumors need to stop the adaptive immune cells from killing them. They do this by manipulating TAMs into disabling the adaptive immune system. Since normal alternatively activated macrophages need to resolve ongoing and destructive immune responses, they have the ability to inactivate, or deactivate adaptive immune cells, a function that is maintained in TAMs. By commandeering this function of TAMs, the tumor cells are able to evade destruction at the hands of adaptive immune cells.

Although we can treat primary tumors successfully, limited treatments exist for metastasis. Metastatic progression involves the shedding of tumor cells from the surface of the primary tumor, migration through the circulatory or lymphatic systems, and colonization and sustained growth at secondary sites. The first thing that tumor cells need to do during metastasis is detach from the primary tumor, but they cannot do this themselves. In addition to this, they need help migrating into the secondary organ, and also support for survival and growth at the metastatic site. As you may have deduced, the tumor cells can achieve all this by enlisting macrophages. In order to create new blood vessels, and patch up damaged tissues, the normal alternatively activated macrophages often need to demolish some tissue areas, for example during tissue reconstruction, in scientific terms this is called extracellular matrix (ECM) degradation, and again this function is retained in TAMs. Specific types of factors are employed to facilitate ECM degradation, these factors are called proteases. The tumors manipulate the TAMs to secrete proteases which have a dual role; they enable the detachment of tumor cells from the primary tumor, and also destroy the surrounding tissue to create a channel through which the tumor cells can more easily migrate into the blood and lymphatic systems. It has even been proposed that TAMs actually lead the tumor cells towards blood vessels by sending out signals that the tumor cells can follow. These signals are mediated by the cytokine and chemokine families of molecules. In addition to this, new research has suggested that macrophages may also support tumor survival and growth at metastatic sites. Macrophages associated with tumors at metastatic sites are called metastasis-associated macrophages, or MAMs. New research indicates that MAMs in the lung are also manipulated by tumors to carry many of the processes I have described above, such as angiogenesis and ECM degradation, as well as the secretion of growth factors and cytokines and chemokines, and this helps migrating tumor cells to invade, survive and grow in the lung, and possibly other organs.

The thought of our own immune system helping the tumors grow, rather than fighting and destroying them, may at first seem very grim. However, this new research is not as disheartening as it sounds. In fact, the discovery that tumors manipulate immune cells into helping them is an enormously significant finding, and has drastically affected the way we look at developing new cancer therapies. It also has important implications for modifying and improving existing ones. For example, let us look at chemotherapy and radiotherapy, currently two of our most successful cancer treatments. Although chemotherapy and radiotherapy are fairly successful in reducing and/or abolishing tumors initially, relapse and recurrence are far too common. It has been proposed that there is a prolonged increase in the recruitment of alternatively activated macrophages after chemotherapy or radiotherapy and that this promotes tumor regrowth and recurrence. In addition to this, it is possible that this increased macrophage recruitment can also promote growth of metastatic tumors. Hence, a combination therapy targeting macrophages along with chemotherapy or radiotherapy may be more effective. This type of treatment has recently started in clinical trials. Although it is too soon to assess its effectiveness, it opens up desperately needed new avenues for the treatment of metastatic cancers, which have thus far had limited treatment options. However, targeting macrophages is tricky because we need functioning macrophages to sustain a working immune system. There is a way to overcome this problem. We now know that TAMs express different genes to normal macrophages. This may allow us to inhibit the functions of TAMs and MAMs in tumors and/or metastatic sites without affecting the functions of normal macrophages, and a lot of research now is trying to identify cancer-associated targets in TAMs or MAMs. The phenotypic flexibility of macrophages may also allow us to manipulate them into turning against the tumors, which could activate the adaptive immune system, hopefully leading to a two pronged attack. Aside from the implications for cancer treatment, we could also utilize macrophages to develop new detection methods for cancers. It is very well known that the earlier the tumor is detected, the more effective the treatments are, and although there have been substantial advancements in the development of tumor detection methods; there is still room for improvement. We know that tumors manipulate macrophages; we know that these manipulations induce changes in macrophage function, and we also know that TAMs are different from normal macrophages. Researchers are now developing methods to utilize these tumor-induced changes in macrophages and TAMs to screen for the presence of tumors and possibly find tumors at earlier stages.

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