The Biology of Cancer
These notes are from the final third of the Spring 1995 Biology of Cancer class
given at Berkeley.
Tumor Immunology
Cell types involved in immunity
- B-Cells
- T-Cells
- Natural Killer Cells
- Macrophages
- Changes in Antigenicity of Tumor Cells
- Transplantation Biology
- Experimental Tumors and the Immunosurveillance Theory
- How Do Spontaneous Tumors Arise in Immunocompetent Hosts?
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Background Information: The immune response is the ability of the body to identify and selectively eliminate or neutralize a foreign invader.
This ability depends on the body's capacity to distinguish self from nonself entities.
The cells of the immune system are formed from stem cells present in the thymus and in the bone marrow.
Cell types involved in immunity
- B-Cells originate in bone marrow. Each B-cell recognizes and produces antibodies for a single antigen. B-cells also form memory cells when stimulated with an antigen, enabling the body to respond more quickly the second time it encounters a substance. B-Cells are responsible for Antibody-Mediated Cell Cytoxicity.
- T-Cells originate in the thymus and are responsible for cell-mediated immunity.
- Killer T-Cells, or CD8+ cells, secrete a cytotoxin which directly kills the targeted cell
- CD4+ cells stimulate other cells.
- Helper T-Cells stimulate B-Cells to proliferate and produce antibodies
- Inflammatory T-Cells activate macrophages to destroy vesicular material.
- Natural Killer Cells are the body's first defense against a foreign invader. Unlike Killer T-Cells, Natural Killer Cells also have the ability to destroy the body's own cells. This may be one way in which the body can keep an emerging tumor in check.
- Macrophages secure foreign invaders in their vesicles and present sample peptides to Inflammatory T-Cells. If the Inflammatory T-Cells recognize the invader as foreign, they can signal the Macrophage to destroy the material in the vesicle.
Change in Antigenicity of Tumor Cells
The cellular changes which cause normal cells to become tumor cells can also result in a change in the signalling molecules which are present on the cell surface. For this section, since "normal" signalling molecules can invoke immune responses if they are expressed at an inappropriate time, "antigen" will be used as a general term which includes both signalling molecules and foreign receptors-- in short, any molecule which can bind to a receptor on a lymphocyte.
- Loss of an antigen: If a tumor cell loses its B7 antigen, it can't invoke the cell-mediated immune response and therefore can't be destroyed by Killer T Cells.
- Addition of an antigen: New proteins can be produced as a result of mutation. If B7 is still present in the cell, this can invoke the immune response and aid in supressing the emerging tumor.
- Reexpression of embryonic antigens: Genetic alterations can lead to the expression of genes which would normally be turned off.
Tumor Antigens
- Tumor-Specific Transplantation Antigen (TSTA): A completely novel antigen, present in tumor cells but not in normal cells
- Tumor-Associated Antigen (TAA): Found in tumor cells, and only present in normal adult cells in very small quantities (for example, reexpressed antigens)
Transplantation Biology
In a population of "ordinary" lab rats, both tumor cells and normal cells are rejected if transplanted into a new host. The mechanism of rejection of normal transplanted cells has been studied in order to shed some light on immunoreaction to tumors.
Autotransplantation of tissue from one part of a host to another. In this case, the transplantation is always accepted.
- Syngenetic mice, in which the host and donor are very similar genetically, as in inbred strains of mice. In this case as well, transplants are accepted.
Heterogenic (Xenogenic) transplants, in which the host is from a different species than the donor. In this case, the transplants are rejected.
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Allogenetic transplants, where the host is of the same species as the donor, but they are genetically nonidentical. Here as well the transplants are rejected. This situation most closely resembles that of tumor formation, where the tumor population is of similar but not identical genetic makeup as the host. In Allogenetic studies, the immune rejection is found to be cell-mediated.
Experimental Evidence for Cell-Mediated Immunological Response to Tumors
- Experimental animals immunized with a chemically induced tumor will reject grafts from the same tumor, but will not reject other tumors induced by the same chemical in the same donor.
- Newborn (prior to the development of an immune system) or irradiated mice can be injected with bone marrow cells from another strain of mice. The injected mouse will be chimeric and can accept transplantations from the other strain. This phenomena is known as Immunological Tolerance.
Experimental Tumors and the Immunosurveillance Theory
- The cells in chemically induced tumors have different antigens each time that chemical is used to cause a tumor.
- Virally induced tumors have the same antigens for each tumor caused by that virus.
Background Information: Both types of experimental tumors have antigens which are different from those of normal cells. This data suggests that chemically induced tumors rise from random changes in the cell, while virally induced tumors rise from a very specific change in the cell which is coded into the virus' genome.
The Immunosurveillance Theory
Postulated by Barnet & Thomas. This theory suggests that the immune system itself evolved as a surveillance mechanism for rejecting emerging tumors which are antigenically different. Without this mechanism, the theory suggests, all organisms would die of tumors shortly after birth.
Emergence:
The evidence which suggested this theory is as follows:
- Tumors generally grow in older organisms, whose immunity is depressed
- Allogenetic grafts are rejected by cell-mediated immunity
- Immunosupressed (through drugs, as in after an organ transplant) or genetically immunodeficient hosts have a higher incidence of tumors
- Chemical and viral carcinogens can supress immunity
- Thymectomy (removal of the thymus, and therefore the T-cells, creating an artifically immunodeficient host) leads to a rapid incidence of tumors
The conditions which are necessary for this theory to be accurate:
- TSA's and TSTA's must be present in all tumors
- Altered tumor cells must evoke immunity very early
- Tumor incidence should vary inversly with T-Cell competence
Status:
The present criticism for the theory is as follows:
- Spontaneous tumors do not seem to have TSA's and TSTA's
- Hewitt's transplant studies: Unlike experimental tumors, most spontaneous tumors are not rejected when transplanted into a similar host. The exceptions are melanoma, lung cancer, and bladder cancer, which are usually induced by environmental hazards such as UV, smoke, and dye respectively.
The present support for the theory is as follows:
- Tumor incidence is inversely proportional to T-Cell competence.
- Young organisms, with low immunocompetency, are more susceptible to tumor viruses.
- Humans who have gone through immunosupression therapy for transplants have a higher risk of developing tumors, even long after the transplant
- Athymic mice (with no T-Cells) are not more susceptible to tumors: a high correlation has been shown between Natural Killer Cells and tumor rejection
The immunosurveillance theory has neither been proven nor disproven at this time. However, regardless of whether the immune system emerged specifically to combat tumors, it is clear that the immune system does have some ability to combat emerging tumors. Given this information, the following question presents itself:
How Do Spontaneous Tumors Arise in Immunocompetent Hosts?
The following evidence argues for the possibility of immune reactions against tumors:
- Spontaneous regression of tumors
- Tumor tissues often contain a large amount of lymphocytes, known as Tumor Infiltrating Leukocytes. When purified and reinjected into the host along with Interleukin 2, these cells are 50-100 times more effective in lysing tumor cells than Lymphokine Activated Killer Cells
- A decrease in cell-mediated immunity leads to faster tumor growth
- There is a higher incidence of cancer in immunodeficient hosts (both genetic and induced immunodeficiency).
The following theories have been presented as to how spontaneous tumors evade the immune system:
- Developing tumors lack TAA's or TSTA's. However, with oncogene activation, new proteins are being expressed, so one would expect changes in the proteins bound to the cell surface. One possible explanation to save this theory is that the newly expressed TAA's are very weak.
- Tumors are always progressing, so cells which are immunoresistant are selected to survive
- Tumors escape cell-mediated immunity through loss of the MHC I gene product. Some tumors which have been studied, like cervical cancer and teratocarcinoma do lack the MHC I product and therefore cannot stimulate T-cell immunity. Transfection of the MHC I gene into the tumor cells can slow their rapid growth.
- Tumors escape cell-mediated immunity through loss of the B7 gene product necessary for costimulation. This appears to be the case for most epithelial carcinomas.
The following methods have been tried to stimulate immune response to tumors:
Active Immunization: Dead tumor cells are reinjected into the original host. Has not been shown to be effective.
Passive Immunization: Antibodies against specific growth factors and receptors are stimulated. Also has not been shown to be effective.
Nonspecific Immune Boosting:
- Cytokines/Lymphokines, such as
- Interferons, produced by B-Cells, T-Cells, and Macrophages after exposure to a tumor virus or tumor cells. Interferon therapy has had some success, especially against Hairy Cell Leukemia.
- Tumor Necrosis Factors (TNFs)
- Interleukin 2 is produced by T-Cells. It has the following effects:
- proliferation of T cells
- activation of monocytes (Lymphokine Activated Killer Cells)
- makes blood vessels more porous so that leukocytes can pass through.
- Reduction of interfering EMF secretion (?)
One problem with Interleukin 2 therapy is that it must be continually administered. This substance in high doses is very toxic systemically, due to its debilitating effects on local growth factors.
- BCG vaccine, which has been partially effective in some melanomas
Last revised: 1995 May 5 by
sev@byz.org