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Immunology
Tumor immunity
TUMOR-ASSOCIATED ANTIGENS
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
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Calmette-Guérin, a bovine mycobacterium) into surface melanomas can lead to their partial
regression. Immunomodulators, such as interleukins and interferon, 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. Another approach to cancer immunotherapy involves the use of tumorinfiltrating 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.
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BODY DEFENSES AGAINST CANCER
Although there is no single satisfactory explanation for the success of tumors in escaping the
immune rejection process, it is believed that early clones of neoplastic cells are eliminated by
the immune response. The growth of malignant tumors is primarily determined by the
proliferative capacity of the tumor cells and by the ability of these cells to invade host tissues
and metastasize to distant sites. It is believed that malignant tumors can evade or overcome the
mechanisms of host defenses. Tumor immunity has the following general features:
1. Tumors express antigens that are recognized as foreign by the immune system of the tumorbearing host.
2. The normal immune response frequently fails to prevent the growth of tumors.
3. The immune system can be stimulated to kill tumor cells and rid the host of the tumor.
Host defense mechanisms against tumors are both humoral and cellular. Effector mechanisms
include the following:
• T lymphocytes
• Natural killer cells
• Macrophages
• Antibodies
T Lymphocytes
Cytolytic T lymphocytes (CTLs) provide effective antitumor immunity in vivo. CTL-mediated
rejection of transplanted tumors is the only established example of completely effective specific
antitumor immunity in vivo. Mononuclear cells derived from the inflammatory infiltrate in
human solid tumors, called tumor-infiltrating lymphocytes, also include CTLs with the capacity
to lyse the tumor from which they were derived. CD4+ T cells may play a role in antitumor
responses by providing cytokines for effective CTL development.
Natural Killer Cells
Natural killer (NK) cells can be activated by direct recognition of tumors or as a consequence of
cytokines produced by tumorspecific T lymphocytes. These cells use the same lytic
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mechanisms as CTLs to kill cells but do not express T cell antigen receptors, and they have a
broad range of specificities. Research has also focused on the role of IL-2–activated NK cells in
tumor killing. These cells, referred to as lymphokine-activated killer cells, are derived in vitro
by culture of peripheral blood cells or tumor-infiltrating lymphocytes from tumor patients with
high doses of IL-2. NK cells may play a role in immunosurveillance against developing tumors,
especially those expressing viral antigens .
Macrophages
Activated macrophages produce the cytokine tumor necrosis factor. As the name implies, TNF
can kill tumors but not normal cells. TNF kills tumors by direct toxic effects and indirectly by
effects on tumor vasculature.
Antibodies
Antibodies are probably less important than T lymphocytes in mediating the effect of antitumor
immune responses, but tumor-bearing hosts produce antibodies against various tumor antigens.
These serve as tumor markers. Although malignant tumors may express protein antigens that
are recognized as foreign by the tumor host, and despite the fact that immunosurveillance may
limit the outgrowth of some tumors, the immune system often does not prevent the occurrence
of cancer. The simplest explanation is that the rapid growth and spread of a tumor overwhelm
the effector mechanisms of the immune response.