Why Listeria?
Listeria monocytogenes is a common bacterium that is often associated with food poisoning. We have evolved in an environment in which Listeria is present in the soil and many of our foods (leafy vegetables, dairy products, meat), and we have a complex and effective immune relationship with it. Most people encounter Listeria in their food routinely and never know it because Listeria is capable of stimulating a very strong cell mediated immune response which eliminates the microbe before it can do any damage. [A cell mediated immune response is the same type of immune response that can be used to kill and clear cancer cells, which is what drew our attention to this microbe in the first place.] Listeria is not very infectious, and people do not spread Listeria from one to another. However, Listeria can cause disease in people who are immuno-suppressed, such as 3rd trimester pregnant women or HIV patients. In these cases Listeria can be fatal, which indicates how strong our immune response is to Listeria: normal people do not realize they have ingested the bacterium, but immunocompromised people can have a fatal response.
Like most bacteria, Listeria is a very strong stimulator of innate immunity, which is a non-specific way to getting the immune system ready to face any threat. Innate immunity sets the stage for an adaptive immune response, which is one directed against a specific target, and usually the stronger the innate response the stronger is the adaptive response. Agents that stimulate innate immunity are called immuno-adjuvants (or just adjuvants), and many technologies currently in development require the use of adjuvants. Our vaccines do not require the use of additional adjuvants because the innate immune response to Listeria is so strong that it elicits the release from the body of many of the chemicals other treatments use as external adjuvants.
Listeria has a unique life cycle. It infects Antigen Presenting Cells (APC), which are the cells that activate immune cells and tell them what to attack. Because of this, Listeria becomes perfectly positioned to have the maximum effect on the immune system in terms of directing it against specific targets. Even more unusual is Listeria's ability to stimulate both helper T cells (CD4+) and killer T cells (CD8+), since both are necessary for an antitumor response and it is unusual for a single pathogen to stimulate both in the way Listeria does.
Antigen Processing Cells normally engulf foreign elements to remove them from the body and present them to the immune system.
Following their ingestion, they are encapsulated and digested in a structure called a phagolysosome (see below). Fragments of the digested invader are used to stimulate the immune system through the exogenous pathway (exogenous; since the invader came from outside the cell).
This pathway is associated with the formation of MHC class II complexes and the activation of specific CD4+ helper T cells directed against the invader. This is the most common response to a foreign invader.
A certain percentage of Listeria, however, are able to break out of the phagolysosomes and enter into the cytoplasm of the cell, where they are safe from lysosomal destruction. After escaping from the phagolysosome, the bacteria are now virulent, and multiply in the cell. Additionally, Listeria is able to migrate into neighboring cells and spread without entering the extracellular space.
Once in the cytoplasm, Listeria is capable of stimulating the immune system via the endogenous pathway (endogenous; because Listeria is now living within the cell). The endogenous pathway is associated with MHC class I complex formation and resultant CD8+ killer T cells.
Listeria also has other very useful effects. In the bone marrow, Listeria induces the synthesis of new myeloid cells that are essential to immune function. In the blood and tissue and they cause the maturation of immature myeloid cells, like dendritic cells, which are most powerful APC and are essential for a strong antitumor response. They also have an effect on blood vessels that allows activated immune cells to leave the blood and enter tumors in a way that increases an immune anti-tumor response.
Perhaps most interestingly is Listeria’s ability to alter the tumor microenvironment. It is now known that stimulating the immune system is not sufficient by itself to treat cancer because tumors have the ability to turn off activated immune cells once they get into tumor tissue. Tumors create within themselves this immune privileged space, which Listeria vaccines can reverse. This enables the strongly activated immune system that Listeria stimulates to be effective within tumors, something other technologies cannot do.
Thus, Listeria has the ability to stimulate multiple limbs of the immune response simultaneously and in an integrated way that serves to bring a number of immune mechanisms together to attack cancer.
