Why Cancer Thrives in the Lungs

Lung Cancer

One reason cancer is so terrifying is that the disease travels. Whether starting in the bone, on the skin, or anywhere else, when a tumor grows large enough it sends out cells to become new tumors in far reaches of the body. Nearly 90 percent of cancer deaths result from this process - metastasis - where tumors spread into new organs.

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Metastasis is particularly mysterious because our body has a powerful immune system that seeks out, and destroys, foreign invaders – including cancer. T cells attack cancer just as they attack the cold virus or E. coli. However, unlike those diseases, tumors have a number of tricks they use to tell the immune system to go away.

Metastasizing cells are less protected, and yet they somehow still find their way to "safe" spaces in the body. Decades of clinical experience show that the lungs are a favorite target of wandering cancer cells, especially for certain cancers like melanoma, breast cancer, pancreatic cancer and colon cancer. Sadly, once cancer spreads to the lungs, it is incredibly difficult to treat.

Breathing easy
What we wanted to learn is why some parts of the body are safer to cancer than others. Through studies in mice, our research at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute examined how the immune system functions in the lungs, and what we learned was revealing: in that environment, T cells are primed to go easy on invaders.

The underlying chemistry, triggered by oxygen, signals T cells not to overreact. It makes sense – if our defenses attacked every foreign object with equal fervor, then we'd never survive allergy season in the spring. As our breath filled with countless particles of pollen and mold, none of which belongs in our body, the immune system would launch so many attacks in our lungs that the organs would be destroyed. And yet, if our immune system didn't attack any invaders, we'd soon be overrun by microbes.

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In our study, recently published in the scientific journal Cell, we showed that the same mechanisms keeping the immune system from swarming clouds of pollen also allow cancer cells to travel, and grow in the lungs. We found that the process that controls those responses involves a chain of reactions, with one of the key components being oxygen – and the lungs have plenty of oxygen.

Training the T cells
Some of our body's best protectors are our T cells, and one way they are controlled in lung tissue is by the activity of prolyl-hydroxylase domain (PHD) proteins. They are highly sensitive to oxygen, and when a lot of oxygen is present, the proteins temper the T cell response. So with this process, humans evolved to survive allergy season, but with the side effect of a relatively immunity-free environment that metastatic cancer can hide in.

However, this discovery points to a potential new approach to cancer treatments. If doctors can carefully control PHD proteins, they can allow T cells in the lungs to do their job. The trick is finding the right balance.

Completely knocking out PHD proteins would trigger an overreaction in the lungs, and cause runaway inflammation that could be as deadly as the cancer. However, by combining treatments to temper PHD proteins boosts to the immune system, it may be possible to prevent many lung tumors from ever taking hold.

The approach would match well to a rising star in cancer treatment, adoptive cell therapy (ACT). In ACT, some of a patient's immune cells are extracted, trained to fight an invading cancer, and then re-injected into the body. When the cancer's usual tricks no longer work, the immune system can fight effectively, and in many cases, the patient may be cured.

If ACT is combined with an approach that carefully manages PHD proteins, a patient would benefit from a tougher immune system and the removal of a cancer "safe haven" in the body. Our study looked at this approach in mice, and the results were promising – the next step is to learn whether the treatment can help people.

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