"The Three Es" Hypothesis of Tumor Immune Surveillance

Cancer Immunoediting: The three Es Hypothesis

Okay, here is post number two, and I am truly sorry for the delay, I have been working (yes really!). Also, in response to comments from dearly valued readers, I am going to try and make this less technical. Which should be easy, considering that I am going to try and explain the concept I read in an amazing review. So, no data parsing. Whew.

Cancer and the immune system have been co-existing for centuries, which is one of the most remarkable-and challenging-aspects of cancer biology. Basically, cancers occur when some cells in the body transform (that is the technical term) and become malignant, upon which they are no longer subject to the basic social rules that govern other, normal or untransformed, cells. Such as, stick to your own tissues, stop growing when told to, do not invade the rest of the body, do not divert the body’s blood vessels to give yourself nourishment and so on. Transformation of normal cells into cancerous ones can occur for a variety of reasons, such as radiation, carcinogenic chemicals, infection with an “oncogenic” virus that specializes in transformation of cells or a random, spontaneous mutation that results in a transformed cell with its attendant anti-social behaviour. This is really simplified and I but brush the surface, but you get the picture: a random event, often a mutation in the body’s own cells can lead to cancer, as both radiation and many carcinogenic chemicals cause cancer by causing mutations.

Here’s the rub: mutations occur frequently. Frequently! When cells divide, they duplicate their DNA and make mistakes while doing so, resulting in mutations. DNA damaging agents, like chemicals and radiation, cause hundreds of mutations, many of which are not productive, in that the cell’s DNA repair machinery kicks in and fixes it (That awesome machinery is the subject of a whole new discussion some day, immunology or not). Even so, transforming events are not rare, and that means we should get cancers more often that we do, and the fact that we don’t has led to much speculation on why. One of the earliest hypotheses on the role of the immune system in cancer, the “immunosurveillance” hypothesis proposed that, in immunocompetent hosts, the immunes system is patrolling the body for sign of transformed cells and eliminates them upon detection, and its only rare ones that get free to cause cancer.

Side note: Immunology, more than other fields of Biology, has the habit of coining terms that are more than likely to send you spell check into a hopeless tizzy. It’s a simple strategy really, just add the prefix immuno- to any English word and you have a whole new term. Immunosurveillance therefore means “surveillance by the immune system” and immunocompetent means “in possession of a competent immune system”.

The biggest problem with the idea of immunosurveillance is that it is, in the words of its proponent Lewis Thomas, “it cannot be shown to exist in experimental animals”. To quote the authors of the review I refer to below, “…how could such an invisible process be experimentally revealed?” If the immune system does actually patrol at steady state and eliminate transformed cells, how do you demonstrate it? The short answer is, using immunodeficient (see!) mice, made possible by sophisticated modern genetic techniques. These immunodeficient mice developed tumors much more frequently than their immunocompetent counterparts. In the interests of full disclosure, there was one study that directly contradicted this one but was then refuted by four groups. Anyway, so Robert Schreiber’s group found evidence for immunosurveillance.

The “three Es hypothesis” comes from this idea, and has been proposed by Schreiber and colleagues. They extend the concept of immunosurveillance to one of immunoediting, which is not the most intuitive title, but bear with me. The idea is that immunosurveillance is one phase of a more comprehensive process-immunoediting-which can be broken up into three component phases: elimination, equilibrium and escape. In the elimination phase, immune cells recognize and eliminate transformed cells. Generally, this is sufficient. After, or simultaneous with, the elimination phase, is the equilibrium phase in which the tumor cells and the immune system exist in an equilibrium of inaction: the tumor doesn’t grow and the immune system doesn’t attack it. This can continue for years, and the individual remains cancer free. Then, some tumors escape. This last phase occurs when a tumor mutates sufficiently to evade elimination by the immune system and grows out. The interesting thing that Schreiber and colleagues propose is that the cues the tumor receives during the elimination and equilibrium phases drive the evolution of escapes: that if the immune system fires bullets, tumor cells learn to make Kevlar and escape. The result is cancer.

This was a really good paper to read, and it is a really interesting idea. There is good data to support the existence of the elimination and escape phases, but the equilibrium phase remains hypothetical and will be hard to demonstrate. The basic idea is logical; at least it seems so to me, neat and believable. However, it unlikely to be the whole story. The hugest caveat with studying tumor immunology is the fact that tumor cells or basically ones own cells that have gone berserk. The immune system has extensive, elaborate machinery in place to ensure precisely that it doesn’t attack its own host body. How then is it supposed to tell that tumor cells are foreign? This is the million-dollar question in tumor immunology and for all the promise that tumor immunotherapy has- after all what could be better than using one’s own cells to combat cancer? -It is unanswered.

Paper referred to:

Dunn G.P., et al. The Immunobiology of Cancer Immunosurveillance and Immunoediting. Immunity. 2004. Volume 21, p137-148.