From My Lawyers (not really)
Allow me to open with a warning. Because I am not a physician, and, in fact, don't have any medical training at all, I'm not a source to be trusted for medical advice. For those readers who are afflicted with cancer, or have relatives or friends with the disease, seeking the opinions of a good oncologist is the best source to learn about therapeutic options. My goal in writing this blog is not to offer therapeutic guidance. It is, first of all, to help me to learn this extremely interesting area of molecular biology. And secondly, to help others do the same. The only way that this work might offer some direction to cancer sufferers is by providing a broad overview of the basic science behind many of the therapies that might be offered. It also might help to point to future developments. But it certainly shouldn't be relied on for concrete medical advice. At all.
As we've seen, the immune system exists in order to defend against foreign invaders. As such, it must somehow distinguish the aliens from the natives. If it fails this task, it risks autoimmunity, often with grave consequences. With respect to cancer, there's the rub. That's because cancer cells are not foreigners. They're normal cells that have acquired mutations and lost their way. As I've found, this problem of telling the good guys from the bad, killing off the enemy without doing collateral damage, is the biggest problem faced by immunotherapy (and other therapies as well).
Despite the fact that cancer cells and normals share most biochemical features, there is good evidence that tumors can elicit an immune response. One piece of evidence comes from studies with chemically induced cancers in mice. If such a tumor is totally removed and transplanted into a closely related sibling, the tumor will grow and eventually kill. If, on the other hand, the tumor is transplanted back into the original mouse, it will often fail to survive. Of course, mice and humans differ. However, it has long been known that human colon tumors are often surrounded by both killer and helper T cells, indicating that the tumor has elicited an immune response. In those cases where such infiltration hasn't occurred, it is associated with a poor prognosis. Another piece of evidence indicating that the immune system does respond to cancer comes from the observation that immune compromised individuals are more prone to cancer than people with an intact immune system.
Despite these studies and observations, it's obvious that the immune system often fails to prevent cancer. There are several reasons for this inability to fend off the disease. First, cancers have several direct strategies to thwart an immune response, a topic that I'll come to later. Second, the immune response may simply lack the power to overcome some cancers. And third, because cancer is an evolutionary disease, the cancer may change its dress, hiding those antigens that evoked the immune response in the first place.
At least four questions come immediately to mind. What are the antigens that that the immune system detects in tumors? Which arm of the immune system is used to attack tumors? What mechanisms do tumors use to mitigate the immune response? What strategies have oncologists developed to strengthen the immune system so that it can better ward off cancer?
Cancer is a disease caused by mutations in the genome. Often these mutations are in the protein coding region of one or more genes, thereby changing the amino acid sequence of one or more proteins (Not always. Some mutations may occur in the regulatory region of a gene, increasing the concentration of an oncogene product for example. Alternatively, a mutation may wipe out a gene completely resulting in the complete absence of a particular protein, such as a tumor suppressor). In turn, changing the amino acid sequence of a protein will change its three dimensional shape, marking it as foreign and as a potential antigen. The mutation doesn't necessarily have to be in a protein in a pathway that promotes cell proliferation. Frequently, cancers carry mutations in many bystander genes (termed "passengers" by scientists in order to distinguish them from "drivers"). The proteins that result from such derangements in protein structure are called "neoantigens".
However, even proteins that are part of the normal cell repertoire have been shown to become antigens. For reasons not clear to me, proteins overexpressed as a result of the amplification of a gene or because of some derangement in gene regulation may become antigenic. Also, proteins that are expressed in embryos that somehow show up in cancer cells, a not uncommon occurrence, may be marked as non-self by the immune system. These observations raise the prospect that more refined and improved immunological approaches might be developed to ward off oncogenesis.
What are the main components of the immune system that attempt to fend off cancers? And how can these components be manipulated to better serve patients? Those topics are subjects for the next post.