Immune surveillance by macrophages and NK cells

Macrophages and natural killer cells may provide surveillance against some cancers. Hyperactivated macrophagessecrete tumor necrosis factor (TNF), and express it on their surface. Eitherform of TNF can kill certain types of tumor cells in thetest tube. This brings up an important point: what happens in the test tube is not always the same as what happensin an animal. For example, there are mouse sarcoma cellsthat are very resistant to killing by TNF in the test tube.In contrast, when mice that have these same sarcomas aretreated with TNF, the tumors are rapidly destroyed.Studies of this phenomenon showed that the reason TNFis able to kill the tumor when it is in the animal is thatthis cytokine actually attacks the blood vessels that feedthe tumor, cutting off the blood supply, and causing thetumor cells to starve to death. This type of death is callednecrosis, and it was this observation that led scientists toname this cytokine “tumor necrosis factor.”

In humans, there are examples of cancer therapies in which activated macrophages are likely to play a major role in tumor rejection. One such therapy involves injecting the tumor with bacille Calmette–Guerin (BCG), a cousin of the bacterium that causes tuberculosis. BCG hyperactivates macrophages, and when it is injected directly into a tumor (e.g., a melanoma), the tumor fills up with highly activated macrophages that can destroy the cancer. In fact, one way of treating bladder cancer is to inject it with BCG – a treatment which is quite effective in eliminating superficial tumors, probably through the action of hyperactivated macrophages.

But how do macrophages tell the difference between normal cells and cancer cells? The answer to this question is not known for certain, but evidence suggests that macrophages recognize tumor cells that have unusual cell surface molecules. One of the duties of macrophages in the spleen is to test red blood cells to see if they have become damaged or old. Macrophages use their sense of “feel” to determine which red cells are past their prime. And when they find an old one, they eat it. What macrophages feel for is a fat molecule called phosphatidylserine. This particular fat is usually found on the inside of young red blood cells, but flips to the outside when the cells get old. Like old red blood cells, tumor cells also tend to have unusual surface molecules, and in fact, some express phosphatidylserine on their surface. It is believed that the abnormal expression of surface molecules on tumor cells may allow activated macrophages to differentiate between cancer cells and normal cells.

In the test tube, natural killer cells can destroy some tumor cells. In addition, there is evidence that NK cells can kill cancer cells in the body. Natural killer cells target cells that express low levels of class I MHC molecules, and which display unusual surface molecules (e.g., proteins which indicate that the target cells are “stressed”).

There would be a number of advantages to having macrophages and NK cells provide surveillance against wannabe cancer cells. First, unlike CTLs, which take a week or more to get cranked up, macrophages and NK cells are quick-acting. This is an important consideration, because the longer abnormal cells have to proliferate, the greater is the likelihood they will mutate to take on the characteristics of metastatic cancer cells. In addition, once a tumor becomes large, it is much more difficult for the immune system to deal with. So you would like the weapons that protect against wannabe cancer cells to be ready to go just as soon as the cells start to get a little weird.

You would also like anti-tumor weapons to be focused on diverse targets, because a single target (e.g., the MHC–peptide combination seen by a killer T cell) can be mutated, rendering the target unrecognizable. Both NK cells and macrophages recognize diverse target structures, so the chances of them being fooled by a single mutation is small. In addition, macrophages are located out in the tissues where most tumors arise, so they can intercept cancer cells at an early stage. And with immune surveillance, as with real estate, location is everything.

There are problems, however, with macrophages and NK cells providing surveillance against cancer. Macrophages need to be hyperactivated before they can kill cancer cells. That’s what the BCG treatments do: they hyperactivate macrophages. So if a wannabe cancer cell arises at a site of inflammation where macrophages are already hyperactivated, that’s great. But if there’s no inflammatory reaction going on, macrophages will probably remain in a resting state and simply ignore cancer cells. Unlike macrophages, which are found in large numbers in our tissues, most NK cells are found in the blood. Like neutrophils, NK cells are “on call.” And the cells which do the calling are activated macrophages and dendritic cells that are responding to an invasion. So again, unless there is an inflammatory reaction going on in the tissues, most NK cells will just continue to circulate in the blood.

As a tumor grows, it eventually becomes so large that the neighboring blood vessels cannot provide the nutrients and oxygen required for continued growth, and some of the cancer cells begin to die. Cancer cells also die when they accumulate mutations that are lethal. Consequently, at a later stage in the growth of a tumor, dying cancer cells may provide the signals required to activate macrophages, which can then recruit natural killer cells from the blood. So at this point, macrophages and NK cells may play a role in destroying at least some of the tumor cells. In addition, because NK cells do not need to be activated to kill, natural killer cells that are circulating in the blood may be able to destroy either blood cell cancers or cancer cells that are metastasizing through the blood from a primary tumor.

In summary, in some circumstances, macrophages and NK cells may provide surveillance against certain types of cancer cells, and the immune system probably is involved in defending against some virus-associated and blood-cell cancers. In addition, the immune system may reduce the frequency of metastases or may help slow the metastatic process once a primary tumor has formed. However, I believe it is unlikely that the immune system provides significant surveillance against most solid tumors in humans during the initial stages of their development. This is my view, but noteveryone agrees with me on this point.

Дата добавления: 2015-06-04