Mechanism of Tumor Immunity
Carcinoembryonic Antigen & Alpha Fetoprotein
Practice Questions: USMLE & Course Examinations
Animals carrying a chemically or virally induced malignant tumor can develop an immune response to that tumor and cause its regression. In the course of neoplastic transformation, new antigens, called tumor-associated antigens (TAAs), develop at the cell surface, and the host recognizes such cells as “nonself.” An immune response then causes the tumor to regress.
In chemically induced tumors in experimental animals, TAAs are highly specific (i.e., cells of one tumor will have different TAAs from those on cells of another tumor even when they arise within the same animal). In contrast, virally induced tumors possess TAAs that cross-react with one another if induced by the same virus. TAAs on tumor cells induced by different viruses do not cross-react.
MECHANISM OF TUMOR IMMUNITY
Cell-mediated reactions attack these nonself tumor cells and limit their proliferation. Such immune responses probably act as a surveillance system to detect and eliminate newly arising clones of neoplastic cells. In general, the immune response against tumor cells is weak and can be overcome experimentally by a large dose of tumor cells. Some tumor cells can escape surveillance by “modulation” (i.e., internalizing the surface antigen so that it no longer presents a target for immune attack).
The cell-mediated immune responses that affect tumor cells in vitro include natural killer (NK) cells, which act without antibody; killer (K) cells, which mediate antibody-dependent cytolysis (antibody-dependent cellular cytotoxicity); cytotoxic T cells; and activated macrophages. Whether these immune responses function to prevent or control tumors in vivo is unknown.
Tumor antigens can stimulate the development of specific antibodies as well. Some of these antibodies are cytotoxic, but others, called blocking antibodies, enhance tumor growth, perhaps by blocking recognition of tumor antigens by the host. Spontaneously arising human tumors may have new cell surface antigens against which the host develops both cytotoxic antibodies and cell-mediated immune responses. Enhancement of these responses can contain the growth of some tumors. For example, the administration of BCG vaccine (bacillus Calmette-Guérin, a bovine mycobacterium) into surface melanomas can lead to their partial regression. Immunomodulators, such as interleukins and interferons, are also being tested in such settings. One interleukin, tumor necrosis factor-α (cachectin), is experimentally effective against a variety of solid tumors (see Chapter 58). In addition, lymphocytes activated by interleukin-2 (lymphokine-activated killer [LAK] cells) may be useful in cancer immunotherapy.
In addition, monoclonal antibodies directed against CTLA-4 and PD-1 (see “Costimulation Is Required to Activate T Cells” section in Chapter 58) are also effective in enhancing the immune response against cancer cells. CTLA-4 and PD-1 on T cells are inhibitors of the costimulatory response, and antibody against these proteins blocks their inhibitory effect. This enhances the immune response against the tumor.
Another approach to cancer immunotherapy involves the use of tumor-infiltrating lymphocytes (TIL). The basis for this approach is the observation that some cancers are infiltrated by lymphocytes (NK cells and cytotoxic T cells) that seem likely to be trying to destroy the cancer cells. These lymphocytes are recovered from the surgically removed cancer, grown in cell culture until large numbers of cells are obtained, activated with interleukin-2, and returned to the patient in the expectation that the TIL will “home in” specifically on the cancer cells and kill them.
CARCINOEMBRYONIC ANTIGEN & ALPHA FETOPROTEIN
Some human tumors contain antigens that normally occur in fetal but not in adult human cells.
(1) Carcinoembryonic antigen circulates at elevated levels in the serum of many patients with carcinoma of the colon, pancreas, breast, or liver. It is found in fetal gut, liver, and pancreas and in very small amounts in normal sera. Detection of this antigen (by radioimmunoassay) is not helpful in diagnosis but may be helpful in the management of such tumors. If the level declines after surgery, it suggests that the tumor is not spreading. Conversely, a rise in the level of carcinoembryonic antigen in patients with resected carcinoma of the colon suggests recurrence or spread of the tumor.
(2) Alpha fetoprotein is present at elevated levels in the sera of hepatoma patients and is used as a marker for this disease. It is produced by fetal liver and is found in small amounts in some normal sera. It is, however, nonspecific; it occurs in several other malignant and nonmalignant diseases.
Monoclonal antibodies directed against new surface antigens on malignant cells (e.g., B-cell lymphomas) can be useful in diagnosis. Monoclonal antibodies coupled to toxins, such as diphtheria toxin or ricin, a product of the Ricinus plant, can kill tumor cells in vitro and someday may be useful for cancer therapy.
1. Regarding tumor immunity, which one of the following is the most accurate?
(A) Both cytotoxic T cells and cytotoxic antibodies attack human cancer cells.
(B) An elevated level of alpha-fetoprotein is a marker for carcinoma of the lung.
(C) A declining level of carcinoembryonic antigen (CEA) is an indication that the patient’s colon cancer has recurred.
(D) Cancer cells induced by chemicals have new antigens on the surface but cancer cells induced by viruses do not.
(E) Natural killer (NK) cells do not participate in the cell-mediated response to cancer cells because they do not have an antigen-specific receptor on their surface.
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found in the Immunology section of PART XIII: USMLE (National Board) Practice Questions starting on page 713. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.