by Alison Wagner, PhD, Medical Writer
An episode of the TV series The Big Bang Theory featured its lovable group of “nerds” debating who was the bravest character in the Marvel Universe. The know-it-all Sheldon proposed that whoever had to give Wolverine a prostate exam was, indeed, the winner of that dubiously enviable title. Sheldon’s wrong on this one, though, and comic book urologists can relax – Wolverine won’t need the prostate exam.
Wolverine’s primary mutant power is his healing ability.* Healing is a job regulated by the immune system, so we can assume that Wolverine’s immune system is phenomenal, given his healing ability and his resistance to aging and illness. It is this superb immune system that will prevent a future storyline wherein Wolverine deals with a cancer diagnosis.
*Yes, Wolverine also has other mutant abilities, and his claws are awesome. However, without his healing ability, he would not have been able to tolerate the process of fusing “adamantium” to his bones, and the claws would then have remained bone claws and not the super-cool blades that are so emblematic of Wolverine.
The immune system, the body’s major defense system, is intimately involved in cancer. The two major arms of the immune system are the adaptive immune system, including T and B cells that can be considered the “special teams,” and the innate immune system, which is more like the ground troops. The ability to avoid adaptive response is a key feature of the success of cancerous cells. Were our immune systems as excellent as Wolverine’s, our adaptive immune systems would seek out and demolish cancer before it could take hold. Failure of the adaptive immune system to control cancerous cell growth is a phenomenon that has long interested researchers, and advances in that area are discussed in this excellent post by Heather. In essence, Wolverine’s immune response is what we aspire to achieve in the field of immuno-oncology by promoting T-cell activation and targeting of cancer cells.
Advances in immuno-oncology deal mostly in the adaptive immune system (T and B cells); however, the innate immune system plays an even more active role in tumor development. For decades, tumors have been described as “wounds that do not heal.”** Under normal circumstances, the presence of a wound activates the innate immune system, causing leukocytes such as macrophages to quickly migrate to the site of the wound and begin their work of healing. The healing process requires activation of these cells, initiating reparative processes including inflammation and angiogenesis – two key processes also seen in tumor microenvironments. The key difference between wound healing and cancer is that in time, wounds heal and activation and inflammation are resolved, allowing the immune cells to disperse away from the site, and everything returns to normal.
**Clearly, “wounds that do not heal” are an impossibility for Wolverine, who has survived grievous wounds and even being torn in half!
Cancer does not resolve. In cancer, the immune cells do not disperse. In fact, after the initial migration to the tumor cells, they are overwhelmed by inhibitory signals from the tumor cells that alter the the immune cells’ activation state. This reduces cell killing and instead tricks the immune cells into providing pro-growth cytokines*** that actually help the cancer cells proliferate, create new blood vessels, and invade new tissue. These immune cells not only do not destroy the tumor cells – they actively contribute to the microenvironment that helps to sustain and grow tumors. If the immune system is the military of the body, the troops go in to do their job against the enemy (the cancer), but are then brainwashed and forced into supportive roles by that same enemy.
***The immune system is enormously complex. Cytokines can be pro-inflammatory, pro-growth, anti-inflammatory, anti-growth, and so on. to Add to the confusion, the same cytokines can have opposite effects under different circumstances, not all of which we understand. Macrophages in particular have different states of activation, which are still controversial, and produce different sets of cytokines depending on the state. There is even a still-debated state specific to the tumor microenvironment. We have a lot to learn!
This would never happen to Wolverine. With his supercharged immune system, cancer cells would be obliterated immediately and efficiently, the tumor’s inhibitor signals unheeded. His mutant power would protect him from the immune dysfunctions that we mere humans suffer in our fight against cancer. However, we’re catching up. The immune system remains somewhat of a mystery, our knowledge of it lagging behind that of other biological systems. But promising advances such as those in immunotherapy are revealing more and more how we might manipulate it to maybe, possibly, be just a little more like Wolverine.