Tumor escape mechanisms of tumor antigen
tumor immunity
A. Tumor Antigens
Ideally. a tumor antigen should be expressed only by tumor cells and not by normal cells in order to be recognized as foreign by the immune system.
In reality. most tumor associated antigens are overexpressed in tumor cells but are also expressed in smaller amounts in normal cells. The enzyme tyrosinase, for example. is expressed in all normal melanocytes. but much higher concentrations occur in melanoma cells.
Tyrosinase specific T cells that recognize and kill melanoma cells can be found in the blood of some melanoma patients. These T cells are indeed responsible for the depigmentation of the skin (vitiligo) in some melanoma patients. The occurrence of vitiligo frequently correlates with a response to therapy.
Oncofetal antigens. such as alpha fetoprotein and carcinoembryonic antigen (CEA). are present in tumors of the liver and gonads and in various adenocarcinomas. These antigens are strongly expressed during fetal devel opment. but are normally only weakly expressed in adults.
Oncofetal antigens circulate as soluble proteins in the blood of tumor patients and are therefore useful as indicators of tumor progression (tumor markers).
In B cell and T cell lymphomas and leuke mias, clone specific determinants (idiotypes) of the immunoglobulins and of the T cell receptor represent individual and specific tumor antigens. Hence, no reactivity with other tissues is to be expected.
Mutated proteins arising from chromosomal translocations or point mutations, on the other hand, represent completely new antigens (neoantigens). ln t(9:22) BCR ABL translocation of CML, for example. a fusion protein develops between the normal BCR and ABL genes. Pep tides with sequences formed by amino acids of both of these genes can function as true tu mor antigens. Point mutations. which com monly occur in tumor suppressor gene p53 and other cell cycle regulating proteins, such as p16 and p21. also lead to the development of new tumor specific peptides that do not oc cur in normal cells. However. these peptides must ht into the HLA molecules of the tumor cells in order to be recognized by the immune system. Hence, it is possible to have tumors where such tumor specific peptides are present but not presented to the immune system by the individual MHC molecules. True viral proteins produced by HTLV] in T cell leukemia and Epstein Barr virus in some malignant lymphomas are responsible for malignant transformation and are produced by tumor cells. There is clear evidence that these viral products can be successfully recognized by the immune system.
In contrast to single mutated proteins, these viral proteins usually contain a large number of pep tides that are potentially immunogenic, and there is a great chance that some of them will bind to the MHC molecules of the host cells.
B. Immune Escape Mechanisms"
There are a number of reasons for the absence of an effective immune response to tumors. Each autologous protein is degraded within the cytoplasm to form peptides consisting of 9-12 amino acids. These peptides are conveyed by a transport system called transporter associated with antigen processing (TAP)" to the endoplasmic reticulum (ER), where they are bound by class i MHC molecules and presented to CD8+ T cells on the cell surface .
Some tumors may not have tumor peptides that fit into the binding sites of the patient's MHC molecules (1). in tumor cells with defective antigen processing machinery (e.g.. TAP deficiency). tumor peptides are not transported to the endoplasmic reticulum (3) and are not presented on the cell surface.
In many cases. there is a lack of MHC class 1 molecules on the surface of the tumor cells due to the down regulation of MHC genes. As a consequence. the tumor antigens cannot be recognized by cytotoxic T cells (2) Tumor cells are not professional antigen presenting cells. They lack co-stimulatory molecules CD80 and CD86 needed for T cell activation.
Without co stimulation. the presentation of a peptide via the MHC/TCR complex leads to T cell anergy and tolerance (4). Some tumor cells also stop producing tumor antigen to escape an immune response (5). Altema tively. the tumor may produce immunosuppressive substances. such as [L 10 and trans forming growth factor beta B (TGF B) (6). and in some cases. MHC 1 like molecules that inter act with inhibitory ligands on T cells are ex pressed by tumor cells. Recently. regulatory T cells (CD4 CD25 J have been shown to sup press immunoreactivity in patients with solid tumors.
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