How safe is your neighborhood? We assume that the residents in our area are reasonably normal. We don’t worry that a dangerous criminal lurks a few doors down. But on the infinitesimally small chance that a neighbor went berserk, what would you do?

Probably you’d call 911 for police help. After all, we were taught from a young age that we could trust the police. But what if the madman had recruited several cops to come over to the “Dark Side” of the force? Such a situation would be practically hopeless.

As improbable as the above scenario is in real life, it’s something that occurs all too often when a tumor malignancy like prostate cancer (PCa) develops in the body. If a cell “goes berserk” by mutating into cancer and proliferating, it has a dangerous impact on its neighbors. The normal cells and other structures surrounding the growing cancer colony form what is called the tumor microenvironment.

Macrophages

One component of the immune system is a type of circulating white blood cell called a macrophage. The name comes from the ancient Greek words for large (macro) and eaters (phagein). They literally destroy by eating and digesting things that don’t have ID tags (proteins) for being healthy on their surface. This includes cancer cells as well as disease-causing germs, debris from dead cells, etc. In a sense, they are good cops on patrol who can be called into action at a crime scene when the immune system sends out an all-points bulletin.

When it comes to tumors, “Macrophages are a major component of the tumor microenvironment and orchestrate various aspects of immunity.”^[i] When the body’s 911 call for help goes out, they surge into the tumor’s neighborhood, forming a battalion in the tumor microenvironment. Like a SWAT team, they can penetrate the tumor itself. When activated by the immune system’s biochemical signals, they can upregulate (switch on) and enhance important anti-tumor activities:

• Direct destruction of cancer cells
• Emitting biochemicals to call for reinforcements by other types of immune system cells
• Educating killer T-cells by relaying the surface cancer ID tags

However, the cancer cells themselves also produce signaling molecules to recruit the good cops over to the Dark Side. Because macrophages can reversibly change, they are as subject to the cancer’s recruitment as they are to healthy messages. Thus, they can be sabotaged into cancer-promoting activity, which largely consists of generating inflammation in the microenvironment—something that tumors thrive on—and diverting other immune system cells from recognizing cancer and combatting it.

A new approach to immunotherapy

Immunotherapy is a very specialized approach to treating cancer, and an enormous amount of science is devoted to developing various approaches. One area of research is focused on controlling macrophages in order to boost their anti-cancer ability and block their pro-cancer activity.

An excellent example of this is the work of a team of researchers at the University of California San Diego School of Medicine. In order to explore how to manipulate macrophages as a strategy for treating tumors (macrophage-targeted cancer therapy), they investigated the underlying molecular mechanisms by which macrophages are programmed to support cancer’s development. Their study is

…the first to uncover the role a molecule called IRE1? plays in determining whether macrophages promote inflammation in the tissues surrounding cancer cells… The researchers found that IRE1? regulates macrophage activation, determining whether these abundant immune cells secrete molecules that increase inflammation and at the same time produce signals that suppress the immune system. They also discovered that IRE1? boosts levels of PD-L1, a molecule that inhibits other immune cells.^[ii]

To confirm that they were on the right track, the team genetically modified a strain of mice that lack the gene for IRE1? in their macrophages, and implanted melanoma, a deadly skin cancer that spreads and forms tumors in other organs. The mice that were modified survived melanoma better than normal mice who were also implanted with the same melanoma cell line.

Hope for anti-cancer therapy

Senior author Maurizio Zanetti, MD is optimistic that discovering the role of IRE1? is the foundation for keeping macrophages centered on their anti-tumor mission. In pointing out the urgent need to create a viable strategy, Zanetti commented, “The implication for therapy is that, down the line, we might be able to locally inhibit IRE1? to specifically prevent the mis-regulation of the macrophages that infiltrate tumors and thus tip the balance in favor of the immune system rather than the tumor.”^[iii]

Such an approach would be a general approach to tumor cancers, including prostate cancer. We wish Zanetti and his colleagues continued success in their research which will hopefully lead to a breakthrough in macrophage-targeted cancer therapy.

NOTE: This content is solely for purposes of information and does not substitute for diagnostic or medical advice. Talk to your doctor if you are experiencing pelvic pain, or have any other health concerns or questions of a personal medical nature.

References

[i] Poh A, Ernst M. Targeting macrophages in cancer: from bench to bedside. Front Oncol. 2018; 8:49. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5858529/
[ii] “Immune cells infiltrating tumors may play bigger cancer role than previously thought.” Science Daily, June 22, 2020. https://www.sciencedaily.com/releases/2020/06/200622160257.htm
[iii] Ibid.