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The main role of our immune system is to find and eliminate invading pathogens, to kill infectious agents, and to heal the body if wounds occur. Without an immune response we would not have survived as a species. The role of the immune response is often compared to the role of our police services in society. Police keep criminal elements at bay, they offer security and allow societies to grow and flourish. However, looking at numerous Hollywood movies, the view of the good cop might be too naive and ‘bad cops” might spoil this picture.

Does this analogy carry over to our immune response? Unfortunately, it does! In particular in cancer. Current research reveals mounting evidence that cancer is able to actively modify the immune response [1-3] in its favor. Instead of killing cancer cells, immune cells provide growth signals, support blood supply to the tumor, inhibit anti-tumor signaling, and help cancer cells to spread throughout the body. As a result, in late-stage cancers, the immune system has been completely corrupted.

Here are some examples of specific pro-tumor immune responses:

• Macrophages: A key role in the immune response play macrophages (white blood cells). They constantly roam through the body and destroy anything that appears foreign. However in cancer, macrophages have been shown to produce growth signals, they can increase motility of cancer cells, help cancer cells to enter into the blood circulation, allow cancer cells to leave the circulatory system at distant organs and even help to establish metastasis elsewhere. In this context they are called tumor-associated macrophages (TAMs), or metastasis-associated macrophages (MAMs), M2-macrophages, or alternatively activated macrophages.
• T-cells: another important player are regulatory T-cells (Tregs). These cells of the adaptive immune response are called upon once an infection or wound has been healed. They signal to their teammates to shut down the immune response as the wound is cured. In case of cancer, they are misguided in judging that the wound has been healed and they actively discourage any further immune challenge, although cancer is still present.
• Platelets: Platelets are those cells that form blood-clots over wounds to facilitate healing. In the same process, they can form clots over circulating cancer cells, or cancer cell clusters. These clots can protect the circulating cancer cells by sheltering them from fluid induced stress as well as from the attack of natural killer cells. Platelets also release platelet derived growth factors, which can benefit the cancer cells.

The current literature shows many more examples of the pro-tumor role of the immune system, [1-3], and more examples are identified in ongoing research.

Immuno therapies?

Recent hope in the treatment of cancer has been brought forth through the introduction of immuno-therapies. Some cells of the immune system are able to actively fight cancer cells, for example cytotoxic T-cells, M1-macrophages, natural killer cells, etc. These immune cells are masters of navigating the human body, they can find cancer cells everywhere, even at distant metastatic sites. The main idea of immuno-therapy is to identify these anti-cancer immune cells, multiply them in the lab, possibly increasing their fitness as well, and then re-inserting them into the human body. Such a boost of a high concentration of tumor-killing immune cells should kill all cancer cells, right? Unfortunately, this is not fully confirmed in clinical studies [4]. It seems that in many situations the effect is much less than expected, and in some situations, the increased immune response makes things worse. What is missing from the idea of immuno-therapy is a full understanding of the pro-tumor roles of the immune system as outlined above. More research in this direction is needed.

Mathematical modeling

The cancer modelling community is only slowly considering pro-tumor effects of the immune system. A. Friedmann and collaborators were among the first to model M1 and M2 macrophages, followed by R. Eftimie and collaborators with a detailed review and a connection to viral therapies (see references in [7]). K. Wilkie and P. Hahnfeldt [8] noted the importance of the modelling of pro-tumor effects of the immune system. L. Shahriyari summarized her observations on immune support of metastasis in [2] and in my lab, A. Rhodes and I developed a mathematical model for the immune-mediated theory of metastasis [5,6]. The model is based on experimental evidence and it can explain all of the reported mysteries of metastasis, such as the fast growth of metastasis after resection of the primary tumor, the occurrence of metastasis at sites of injuries, the relative low success of immunotherapies, and the preference of metastasis in tissues that are highly immuno active such as bone, liver and lungs.

A mathematical model is not a proof. But it gets us thinking. To view the role of the immune system as anti-tumor only is too simplistic and more details of the complicated interaction of cancer and immune response must be considered. If the pro-tumor effects can be understood and controlled, then there is new hope for immuno-therapies.

All this must be seen in the right context. Our immune system is absolutely amazing and it is able to keep many of us alive and healthy for a very long time. There is a plenitude of good cops in our bodies. It is only those very few bad-cops that, together with cancer, can cause a whole lot of trouble, and I hope we find ways to control them.

References

1. Joyce, J., Pollard, J.. Microenvironmental regulation of metastasis. Nature Reviews of Cancer 9, 239-252, 2009.
2. Shahriyari, L.. A new hypothesis: some metastases are the result of inflammatory processes by adapted cells, especially adapted immune cells at sites of inflammation. F1000 Research 5, 175, 2016.
3. N.K. Altorki, G. J. Markowitz, et. al., The lung microenvironment: an important regulator of tumour growth and metastasis. Nature Reviews Cancer, 19, 9-31 , 2019.
4. Emens, L., Ascierto, P., Darcy, P., et al., Cancer immunotherapy: Opportunities and challenges in the rapidly evolving clinical landscape. European Journal of Cancer 81, 116-129. 2017.
5. A. Rhodes, T. Hillen. A mathematical model for the immune-mediated theory of metastasis. J. Theor. Biol. vole 482, 2019. bioarXiv 10.1101/565531v1
6. A. Rhodes, T. Hillen, Implications of Immune-Mediated Metastatic Growth on Metastatic Dormancy, Blow-Up, Early Detection, and Treatment, submitted 2019. bioRxiv 10.1101/814095
7. R. Eftimie, Bramson, J., Earn, D., 2011. Interactions between the immune system and cancer: A brief review of non-spatial mathematical models. Bulletin of Mathematical Biology 73, 2-32.
8. Wilkie, K., Hahnfeldt, P., 2017. Modeling the dichotomy of the immune response to cancer: Cytotoxic effects and tumor-promoting inflammation. Bulletin of Mathematical Biology 79, 1426-1448.