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Tumor Antigens - IV
Virally induced tumors express tumor antigens shared by all tumors induced by the same virus. When syngeneic mice are injected with killed cells from a particular polyoma-induced tumor. The recipients are protected against subsequent challenge. When lymphocytes are transferred from mice with a virus-induced tumor into normal syngeneic recipients, the recipients reject subsequent transplants of all syngeneic tumors induced by the same virus. In the tumors induced by Sv40 and Polyoma viruses, presence of tumor antigens is related to the neoplastic state of the cell. In humans Burkitt’s-lymphoma, cells have been shown to express a nuclear antigen of Epstein-Bar Virus, a tumor-specific antigen for this type of tumor. Potential value of these virally induced tumor antigens can be seen in animal models. Mice were immunized with genetically engineered polyoma virus tumor antigen and thus shown to be immune to subsequent injections of live polyoma-induced tumor cells. Experimental induction of immunity against tumors have been shown.
Tumor Antigens - V
The majority of tumor antigens are not unique to tumor cells. They also are present on normal cells. Several growth-factor receptors expressed at significantly increased levels on tumor cells serve as tumor associated antigens. A variety of tumor cells express the epidermal growth factor (EGF) receptor at levels 100 times greater than that in normal cells. The gene that encodes p97 has been cloned. A recombinant vaccinia virus vaccine has been prepared, when this vaccine was injected into mice, it induced both humoral and cell-mediated immune responses which protected the mice against live melanoma cells expressing the p97 antigen. Results such as this highlight the importance of identifying tumor antigens as potential targets of tumor immunotherapy. Oncofetal tumor antigens are found not only on cancerous cells also on normal fetal cells. These antigens appear early in embryonic development. If these antigens appear later on cancer cells they are recognized as nonself. Two well-studied oncofetal antigens are
- 1. Alpha-fetoprotein (AFP)
- 2. Carcinoembryonic antigen (CEA)
Serum concentration of Alpha-fetoprotein (AFP) is milligram levels in fetal serum and nanogram levels in normal adult serum. Carcinoembryonic antigen (CEA) is a membrane glycoprotein found on gastrointestinal and liver cells of 2- to 6-month-old fetuses. AFP and CEA can be found in trace amounts in in some normal adults, in some noncancerous disease states.
Tumor Antigens - VI
Many tumors have been shown to express tumor associated antigens encoded by cellular oncogenes. Usually there is no qualitative difference between the oncogene and proto-oncogene products. Increased levels of the oncogene product can be recognized by the immune system. Human breast-cancer cells exhibit elevated expression of the oncogene-encoded Neu protein, a growth factor receptor. Whereas normal adult cells express only trace amounts of Neu protein. Several TATAs have been identified on human melanomas. Each of these antigens is expressed in significant proportion of human melanoma tumors. A number of differentiation antigens expressed on normal melanocytes are Tyrosinase, gp100, Melan-A or MART-1, and gp75. Oncofetal-type antigens are MAGE-1, MAGE-3, BAGE, GAGE-1, and GAGE-2. Several of the human melanoma tumor antigens are shared by a number of other tumors. About 40% of human melanomas are positive for MAGE-1, and about 75% are positive for MAGE-2 or 3. It might be possible to produce a tumor vaccine by expressing the shared antigen for the treatment of a number of these tumors. In experimental animals, tumor antigens can be shown to induce humoral immune responses and cell-mediated immune responses, resulting in the destruction of the tumor cells. Expression of class I MHC molecules is decreased in a number of tumors limiting the role of specific CTLs in their destruction. NK cells and macrophages are important in tumor recognition. The recognition of tumor cells by NK cells is not MHC restricted.
Tumor Antigens - VII
Activated macrophages also play a significant role in the immune response to tumors. Macrophages are often observed to cluster around tumors. Their presence is often correlated with tumor regression. The antitumor activity of activated macrophages is mediated by lytic enzymes, reactive oxygen and nitrogen intermediates. Activated macrophages secrete a cytokine. Immune Surveillance Theory was first conceptualized in the early 1900s by Paul Ehrlich. This theory states that cancer cells frequently arise in the body but are recognized as foreign and eliminated by the immune system. Nude mice, for example, lack a thymus, consequently lack functional T cells. According to the immune surveillance theory these mice should show an increase in cancer. Instead, they are no more susceptible to cancer than other mice. One possible explanation for the selective increase in immune system cancers is that immunosuppressive agents themselves may exert a direct carcinogenic effect on immune cells. Finally, this theory assumes that cancer cells and normal cells exhibit qualitative antigen differences. However, tumors induced by viruses are expected to express some antigens encoded by the viral genome.
Tumor Evasion of the Immune System
Following the discovery that antibodies could be produced to tumor-specific antigens. Attempts were made to protect animals against tumor growth by:
- Active immunization with tumor antigens
- Passive immunization with antitumor antibodies.
These immunizations did not protect against tumor growth. Many cases, they actually enhanced growth of the tumor. Serum taken from animals with progressive tumor growth found to block the CML reaction, serum taken from animals with regressing tumors had little or no blocking activity. Since these first reports, blocking factors have been found to be associated with a number of human tumors. In some cases, antitumor antibody itself acts as a blocking factor. Presumably the antibody binds to tumor-specific antigens and masks the antigens from cytotoxic T cells. In many cases, the blocking factors are not antibodies alone rather antibodies complexed with tumor antigens. Certain tumor-specific antigens have been observed, they disappear from the surface of tumor cells in the presence of serum antibody then reappear after the antibody is no longer present. The phenomenon, called antigenic modulation was readily observed when leukemic T cells were Injected into mice previously immunized.