Saturday, March 27, 2010

Why Doesn't the Immune System Target Tumours?

Recently some people told me about how an Italian cardiologist is making a big fuss out of the fact that when he removes a tumour he finds fungal infections around it, the implication being the fungal infection is causing the tumour. Classic case of mis-attribution of cause. Despite the claims of the news article and\or researchers, this is not news. By way of example, look at the following graphic which is drawn from this research piece.
The article was published in November 2007. Yes, scientists love to claim they were the first to make the discovery! If you scroll down the link above you can download a powerpoint presentation pertaining to this issue. To gain some insight into why this finding is so important, read on.

Regulatory T cells, pictured left, play a cardinal role in preventing inflammation and maintaining the appropriate function of immune processes. For an overview of this function you can read this page from Molecular Immunology. These cells are also very important in preventing autoimmunity. Contrary to popular opinion our immune processes do create a host of cells that are sensitive to self proteins. The most obvious of these is gamma delta T cells, which are very sensitive to both human and bacterial heat shock protein 60. It may seem counter intuitive that immune processes have such functions but it is vital in both defence against pathogens and in removing damaged cells. Heat shock protein 60 is an intrinsic activator of T cell responses. The endocytosis of hsp60, where it is absorbed by cells, can stimulate Toll receptors, key receptors in initiating immune responses and instigated apoptosis(programmed cell death). Significantly, stressed cells can release large amounts of hsp 60 into the extra cellular signal so hsp60 can act as a very powerful "danger signal". Thus, even in the presence of self proteins that help prevent excessive inflammation, the release of hsp60 signals that there are damaged cells which need to be removed. This function can be very important in preventing cancer because the cells are destroyed before they develop the capacity to proliferate.

A note on nomenclature: you may have noticed I prefer not to use the phrase "immune system". The reason for this is that I regard the use of word "system" as misleading because it implies that our immune responses arise from some carefully orchestrated systemic processes. I wish, it is more like a hodge podge of responses that hopefully gets the job done. As history has indicated though pathogens can reek havoc on human populations and our immune processes can take a long time to adapt to new pathogens. I am of the opinion that it is impossible for any single person to have immune processes that can address all potential pathogens. So thankfully we all carry immune processes of varying ability to address pathogens. If not for that a species like ours could not survive for very long. Strike up one for Group Selection, currently out of vogue in Evolutionary Theory. Evolutionary biologists might do themselves a favour by studying physiology in depth, perhaps then they may realise that evolution is not dedicated to singular means of adaptation but rather is a cobbled together set of functions. So natural selection can impact on single genes or networks of genes, or the phenotype, and in the case of immune responses at least, acts at a Group Selection level.


Taking the first graphic as a guide, a key problem is that tumours typically express many self-proteins and this confounds the immune response because these proteins encourage the maintenance of regulatory T cells thereby precluding an immune response against the tumour cells. This can also explain why in rare cases a tumour can suddenly be attacked by immune cells. The balance of signals is upset, in spite of the self-protein presentation by MHC Class 1 receptors and it may well be that proteins like hsp60 play a cardinal role in changing the signal balance. Other "danger signals" that can upset this balance are hsp70,extra-cellular ATP, grp78, and the list goes on ..... . It was noted long ago that occasionally a cancer patient with an infection of some sort(eg. the flu) can demonstrate tumour shrinkage. This occurs because infection typically generates inflammation, a very important component in preventing infection. Inflammation shifts the balance, depleting regulatory and naive T cells and so allowing a more pronounced assault on tumour cells.

In these days we hear a great deal about managing systemic inflammation. With good reason, systemic inflammation markedly increases the risk of cancer, heart disease, dementia, and generally is damaging to tissues. It is something of a Catch 22, maintaining an appropriate balance between inflammation and appropriate immune function is a key area of current research. At the popular level the general presumption is that one should always keep inflammation to a minimum but as the foregoing has demonstrated that is not necessarily always a good thing. The current emphasis on vitamin D is instructive because vitamin D, through its enhancement of tgf beta(tranforming growth factor beta), promotes the creation of regulatory  and naive T cells.

All this highlights the big problem with molecular biology. It can be summed up in one word: quantification. (Unintended pun!) We can perceive these processes but knowing when we should shift the immune balance towards a more inflammatory state is almost impossible to determine. Strictly speaking molecular biology does not qualify as a science and this is because so little can be quantified in a meaningful way that can enable us to determine the appropriate balance of various physiological functions. For example, if you read an earlier post of mine you will see that in the relevant experiment inflammation mediated by interleukin 6 is very important in promoting amyloid removal from the brain, thereby helping to prevent dementia. My personal view is that the desire of some to maintain a specific physiological state ALL the time is probably misguided. It is my belief that despite all the complexity and fancy words we are missing some fundamental features that undergird biological processes. This may well be more a conceptual and\or philosophical problem than an empirical one.

Finally, that Italian oncologist made a mistake all too often made. It was the immuno-suppression around the tumour that allowed the fungal growth, not that the fungal growth was promoting tumour. It is never sufficient to take a research finding and extrapolate from the same unless one has developed a good theoretic framework within which to understand the relevant finding. Unfortunately while there is a welter of health related news in these days it is often presented without a theoretic context, thereby misleading a great many people, including it would seem a certain Italian cardiologist.

The news release via Eureka Alert can be read here.
The abstract for the study is available here.

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