The response of the immune system to cancerous cells is often inadequate because tumor cells use a variety of mechanisms to avoid detection. In their attempt to develop successfull cancer vaccines, scientists must try to create a stronger host immune response. It is important to understand the mechanism of the natural immune response and the ways in which cancerous cells evade detection in order to understand the difficulties of vaccine development. Click here for definitions of some of the basic components of the immune system.
The host immune system must recognize tumor cells as altered self cells before it can mount an immune response against them. Tumor cells display antigen-derived peptides conjugated to Class I MHC molecules on their surface. Though tumors are derived from self tissues, they express two types of antigens whose peptides can be recognized by the CD8+ T cells. Tumor-specific transplantation antigens (TSTAs) are expressed only in tumor cells and, when TSTA peptides are displayed on the cell surface, tumor cells can be recognized and destroyed. Unfortunately, by killing cells that express high levels of TATAs, the immune system actually selects for tumor cells that express low levels of these antigens.
Tumor-associated transplantation antigens (TATAs) are tumor antigens that may be present in very low levels in normal cells or in fetal cells. TATAs that are normally present during fetal development but are otherwise expressed only in cancerous cells are called oncofetal tumor antigens. Alpha-feto proteins (AFPs) and carcinoembryonic antigen (CEAs) are two examples of oncofetal tumor antigens that have been associated with various cancers. TATAs may be recognized as foreign but they are less immunogenic than TSTAs because they are found in some self cells.
The host immune system can be activated when CD8+ T cells form a conjugate with the peptides displayed on the tumor cell surface and when the CD28 on the T cell binds to B7 on the tumor cell.
from Mike
Clark's Immunoglobulin Structure Homepage
Many tumor cells do not have the B7 protein on their surface so this co-stimulatory signal cannot take place. Tumor cells that do have the B7 protein can bind to either CD28 or CTLA-4, both of which are T cell receptors. The B7 protein on the tumor cell must bind to CD28 in order to activate the host immune system. When CD8+ T cells receive both of these signals, they cause a CTL response to occur. Cytotoxic T lymphocytes release perforin which forms pores in the tumor cell membrane. These pores affect ion concentration within the canecerous cell and provide a port of entry for tumor necrosis factor. Click here to view a movie of CTL activity.
Natural killer (NK) cells and macrophage cells can also be involved in tumor destruction. NK cells are capable of lysing a wide variety of tumor cells because they are not MHC restricted. When the Fc receptor on an NK cell binds to a tumor cell, the NK cell facilitates antibody-dependent cell-mediated cytotoxicity (ADCC). When macrophages are activated by IFN-g and macrophage activation factor (MAF), they secret lytic enzymes into canerous cells that can inhibit tumor growth.
Even if cancerous cells possess high levels of immunogenic antigens, they can still avoid detection. Tumor cells can downregulate their expression of Class I MHC and can hide cell surface antigens with glycocalyx molecules. Also, tumor products may supress the anti-tumor immune response and there may be acquired resistance to immune effector mechanisms. Because tumors have many means of evading the host immune system, they are ofen undetected.
Some scientists believe that immunosurveillance, cell monitoring, is constantly taking place within the body. Experimental evidence has neither proved nor disproved this theory, but if there is immunosurveillance, it is clearly not always effective.
