Immune Surveillance

For many years, scientists have debated whether our immune systems can identify cancer or other abnormal cells and destroy them spontaneously. This concept, called “immune surveillance,” suggests that throughout life the immune system constantly examines the surfaces of cells in the body and can tell when a cell becomes abnormal. When it finds an abnormal cell, the immune system has machinery that can attack that cell and destroy it. This clearly can happen with cells infected by viruses, or with cells and tissues transplanted from a non-matched individual. However, there has been debate as to whether this happens constantly with cancer cells. Further, there has been debate as to whether a failure of this system actually could have a role in leading to clinically significant cases of human cancer.

Many years ago, scientists developed mice with defects in their immune systems, such as “nude mice.” If immune surveillance were important, one might expect that mice with poor immunity might have a higher incidence of spontaneous cancers. Surprisingly, when these nude mice were followed for a long time, only a few rare tumor types developed. This result dampened enthusiasm for the existence of such a surveillance system.

However, in recent years, other types of immune deficient mice have been developed and it is now understood that the immune system is more complicated than first thought. The nude mice, for example, while not having T-cells, do have an intact “innate” immune system of other cell types, and are not really completely immunodeficient. When completely immune deficient mice were examined, such as ones that are missing the genes for perforin as described earlier, they do, in fact, develop common tumors at a faster rate. As a result, the last decade has seen a renewed interest in the concept of immune surveillance.

The concept suggests that as cancer cells develop, they are detected by the immune system at a very early stage (perhaps at the stage of a single cell or a few cells) and are then killed and cleared from the body. This actually makes some sense from what we now know about the properties of cancer cells. A hallmark feature of cancer cells is the loss of control of the accurate duplication of their genes, such that they constantly gain mutations. Those mutations that are an advantage to the cancer cell will allow it to survive, so cancers constantly become more and more bizarre as they develop. Such bizarre changes should make the surface of cancer cells very different from normal cells and make them easier for the immune system to detect. This assumes, however, that the cancer cells also do not develop some other property that makes them either invisible to the immune system or actively able to kill immune cells. Both of these defensive tricks by cancer cells may occur.

This concept implies that we are constantly getting cancer (one cell at a time) but the cancer cells do not survive because our immune systems detect and kill them. But only the cancer cells die; normal cells are unharmed. That this could happen with such precision was at first difficult to believe. However, the SR/CR mouse is a direct demonstration that such immune-mediated killing can occur in an otherwise healthy animal. For this reason, this unique mouse provides another bit of evidence that immune surveillance is probably a normal process that protects us from constantly developing cancer.

Cancer Resistance Genes

This mouse also shows that, just as immune deficiency can be genetically determined (inherited immune deficiencies), immune protection can also be genetically determined. We all know that the risk for some types of cancer can be inherited, such as families who have a high frequency of breast cancer, ovarian cancer, etc. Most of the identified familial risk genes are ones that cause tumor cells to grow and survive. Few have been identified that affect how our immune systems can influence cancer incidence although, some inherited immune deficiencies do increase the risk of developing certain forms of cancer.

On the other hand, how would we know that a particular family has a gene that resists cancer? Rather than having a higher incidence of cancer, that family would simply not have cancer. Could we spot such a family? Probably not, since we think of not having cancer as a normal characteristic. The only way to identify such people might be to look at someone with high risk for cancer development, such as through some form of risky exposure (environmental carcinogens) and/or old age (where cancer statistically would be more common).

The SR/CR mouse demonstrates that cancer resistance genes exist and can have dramatic effects on responses to cancer development. This suggests that we should look more carefully for such cancer resistance genes in people, since identifying them (or their absence) could tell us a great deal about how susceptible to cancer we really are.

Why Does Cancer Incidence Rise with Increasing Age?

The difference in efficiency of the cancer resistance mechanism in the SR/CR mice with aging brings up an interesting concept. We think of the increased incidence of cancer in the aging population as a demonstration that mutations are constantly occurring during our lifetimes. It is certainly true that many cancers actually develop over many years before they become clinically detectable. It is also true that many cancers develop as the result of accumulation of stepwise multiple mutations in important genes that control growth of cancer cells. But is this the whole story?

The SR/CR mice show resistance at an early age to cancer cells that have developed advanced and bizarre mutations that allow them to grow in normal mice. Yet, the immune system in the SR/CR mice still can kill them all. But as the SR/CR mice age without being exposed to tumor cells, they naturally lose the effectiveness of this resistance mechanism. Could the same thing influence cancer development in people? Could it be that we constantly reject cancer cells by immune surveillance throughout our lives and, as we age, that mechanism becomes weaker and weaker, until finally one cancer cell overcomes those controls? The SR/CR mouse provides support for the concept that cancer develops not only because of accumulated mutations in cancer cells, but also because immune rejection begins to fail with age. By understanding how this mouse rejects cancer when it is young, we may be able to boost the immune rejection of cancer cells in later life. This might make it possible to do a similar thing in people, and add to our weapons to fight disease in cancer patients.

Spontaneous Regression of Human Cancer

For many years, reports of the spontaneous disappearance of advanced cancer have appeared in the scientific literature. While some could be dismissed as mistaken diagnoses, or unexpected treatment successes, there is a clear body of evidence that such things do, in fact, occur. It happens so rarely that scientists have no hope of being able to study it, since the patient is cured at the time it is recognized and there is no way to do further investigation. What has been lacking in this field is an appropriate animal model in which the regression events could be repeatedly produced and studied in detail. The SR/CR mouse is perhaps such a model and demonstrates at least one way in which this event could happen. Further, it is controlled genetically in an otherwise healthy animal.

Potential Therapies of Human Cancer

The SR/CR mouse is only an animal model. Its use is limited to the laboratory and perhaps only special circumstances, such as transplantation of mouse cancers. For example, we have yet to show that this mouse could reject a tumor that developed in its own tissues, although those experiments are currently under way. Considering that the transplanted tumors used previously are from essentially genetically identical animals, it is probably likely that rejection of naturally occurring tumors will occur. However, a more compelling question is how the knowledge gained from this mouse could be used to benefit human patients.

There are several possibilities. First, the mutation in this mouse will be identified in the future, and a similar gene almost certainly exists in humans. Whether a similar mutation introduced into that human gene would have the same benefit is unknown, but that is the first possible strategy to employ this knowledge. For example, one could take white blood cells of the appropriate type from a cancer patient and one could introduce that mutated human gene into the patient’s cells outside of the body (ex vivo), and then give them back to the same patient. In this way, perhaps, the transferred immune cells might be more effective against the patient’s cancer. Such strategies are complex and will take many years to develop.

Another strategy is to understand the pathways and mechanisms that are used in the mouse to detect and reject cancer cells, and then employ those in a more general way in patients. That is, if a drug could be developed that would enhance a similar immune system component in people, it might be predicted to be an effective anti-cancer therapy.

Another concept is that the loss of resistance to cancer with aging in this mouse may be under some form of predictable regulation. The mouse model may provide a way of understanding how aging affects immune system function. With that knowledge in hand, it might be possible to prevent that loss of function and decrease the rate of development of human cancer.

Conclusions

Whether this mouse model can yield important clues to human cancer will await future experimental results. There are some features, however, that give reasons for at least guarded optimism. The resistance trait is dominant (only one copy of the mutation is needed to see the effect), is very dramatic, and is effective against highly aggressive forms of experimental cancer. The mice are otherwise healthy and have a normal lifespan. The mechanism responsible for resistance can be boosted and can keep older animals resistant much longer than they otherwise would be. In studying this mouse model, we start from a highly successful “phenotype” and only have to work back to understand what is already a successful mechanism. Nature has done the hard part in creating the mutation; it is only up to the scientists studying the mouse to keep an open mind and understand how it did it. We can only be grateful that Nature never read our textbooks.