The immune response to foreign antigens consists of
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Humoral mechanisms (eg, antibodies)
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Cellular mechanisms
Most humoral responses cannot prevent tumor growth. However,
effector cells, such as T cells, macrophages, and natural killer cells,
have relatively effective tumoricidal abilities. Effector cell activity
is induced by cells that present tumor-specific antigens (TSAs) or
tumor-associated antigens (TAAs) on their surface (these cells are
called antigen-presenting cells) and is supported by cytokines
(eg, interleukins, interferons). Despite the activity of effector
cells, host immunoreactivity may fail to control tumor occurrence and
growth.
Cellular Immunity
The T cell is the primary cell responsible for direct
recognition and killing of tumor cells. T cells carry out immunologic
surveillance, then proliferate and destroy newly transformed tumor cells
after recognizing TAAs. The T-cell response to tumors is modulated by
other cells of the immune system; some cells require the presence of
humoral antibodies directed against the tumor cells (antibody-dependent
cellular cytotoxicity) to initiate the interactions that lead to the
death of tumor cells. In contrast, suppressor T cells inhibit the immune
response against tumors.
Cytotoxic T lymphocytes (CTLs) recognize antigens on
target cells and lyse these cells. These antigens may be cell surface
proteins or may be intracellular proteins (eg, TAAs) that are expressed
on the surface in combination with class I major histocompatibility
complex (MHC) molecules. Tumor-specific CTLs have been found in
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Sarcomas
Natural killer (NK) cells are another population of
effector cells with tumoricidal activity. In contrast to CTLs, NK cells
lack the receptor for antigen detection but can still recognize normal
cells infected with viruses or tumor cells. Their tumoricidal activity
is termed natural because it is not induced by a specific antigen. The
mechanism by which NK cells discriminate between normal and abnormal
cells is under study. Evidence suggests that class I MHC molecules on
the surface of normal cells inhibit NK cells and prevent lysis. Thus,
the decreased level of class I molecule expression characteristic of
many tumor cells may allow activation of NK cells and subsequent tumor
lysis.
Macrophages can kill specific tumor cells when activated
by a combination of factors, including lymphokines (soluble factors
produced by T cells) and interferon. They are less effective than
T-cell–mediated cytotoxic mechanisms. Under certain circumstances,
macrophages may present TAAs to T cells and stimulate tumor-specific
immune response. There are at least 2 classes of tumor-associated
macrophages (TAM):
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TAM-1 (M1) cells facilitate T cell killing of tumors
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TAM-2 (M2) cells promote tumor tolerance
M1 and M2 are considered to exist on a continuum until they
maximally differentiate (polarize) into M1 and M2. Such polarization can
vary over time and depends on the stage and type of cancer as well as
treatments.
Dendritic cells are dedicated antigen-presenting cells
present in barrier tissues (eg, skin, lymph nodes). They play a central
role in initiation of tumor-specific immune response. These cells take
up tumor-associated proteins, process them, and present TAAs to T cells
to stimulate the CTL response against tumor. Several classes of
dendritic cells can mediate tumor promotion or suppression.
Lymphokines produced by immune cells stimulate growth or
induce activities of other immune cells. Such lymphokines include
interleukin-2 (IL-2), also known as T-cell growth factor, and the
interferons. IL-12 is produced by dendritic cells and specifically
induces CTLs, thereby enhancing antitumor immune responses.
Regulatory T cells are normally present in the body and
help prevent autoimmune reactions. They are produced during the active
phase of immune responses to pathogens and limit the strong immune
response that could damage the host. Accumulation of these cells in
cancers inhibits antitumor immune responses.
Myeloid-derived suppressor cells consist of immature
myeloid cells and their precursors. These cells increase in number in
cancer as well as inflammation and infection. The cells have potent
immune suppressive activity. Two populations of these cells are
recognized:
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Granulocytic
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Monocytic
Myeloid-derived suppressor cells accumulate in large numbers in
cancers and predict poor clinical outcomes in various types of cancer.
Humoral Immunity
In contrast to T-cell cytotoxic immunity, humoral antibodies do
not appear to confer significant protection against tumor growth. Most
antibodies cannot recognize TAAs. Regardless, humoral antibodies that
react with tumor cells in vitro have been detected in the sera of
patients with various tumors, including
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GI tract carcinomas
Cytotoxic antibodies are directed against surface antigens of
tumor cells. These antibodies can exert anti-tumor effects through
complement fixation or by serving as a flag for destruction of tumor
cells by T cells (antibody-dependent cell-mediated cytotoxicity).
Another population of humoral antibodies, called enhancing antibodies
(blocking antibodies), may actually favor rather than inhibit tumor
growth. The mechanisms and relative importance of such immunologic
enhancement are not well understood.
Failure of Host Defenses
Although many tumors are eliminated by the immune system (and
thus are never detected), others continue to grow despite the presence
of TAAs. Several mechanisms have been proposed to explain this deficient
host response to the TAA, including the following:
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Specific immunologic tolerance to TAAs in a process that involves antigen-presenting cells and suppressor T cells, possibly secondary to prenatal exposure to the antigen
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Suppression of immune response by chemical, physical, or viral agents (eg, helper T-cell destruction by human immunodeficiency virus [HIV])
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Suppression of the immune response by cytotoxic drugs or radiation
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Suppression of the immune response by the tumor itself through various complex and largely uncharacterized mechanisms that cause various problems including decreased T, B, and antigen-presenting cell function, decreased IL-2 production, and increased circulating soluble IL-2 receptors (which bind and hence inactivate IL-2)
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Presence and activity of TAM-2 (M2) polarized cells, promoting tumor tolerance
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