Modulation Mine Docoment

antigenic modulation
Definition:
the alteration of antigenic determinants in a living cell surface membrane
following interaction with antibody.
Loss of detectable antigen from the surface of a cell after incubation

with antibodies. This is one method in which some tumors escape
detection by the immune system. Antigenic modulation of target antigens
also reduces the therapeutic effectiveness of treatment by monoclonal
antibodies.
TUMOR IMMUNE ESCAPE MECHANISMS

Despite presentation of antigens by malignant cells and the presence of
immune cells that could potentially react against these cells, in many cases
the immune system does not get activated but ignores the tumor .
According to the danger model, APC may not get activated in this situation
due to of a lack of danger signals . Other factors may also contribute to
immunological ignorance. The immune system ignores tumor cells, which
fail to migrate to lymph nodes and fail to activate T cells directly . In
addition, tumors growing in immune privileged sites such as the brain or the
eye are not surveilled by the immune system . Down-regulation of adhesion
molecules in malignant tissue may inhibit immune infiltration and thus may
also contribute to immunological ignorance . The tumor stroma has also
been shown to play a critical role . It may serve as a physical barrier
between the tumor and immune cells. Growth of antigenic tumors in the
presence of potent immune cells cannot be explained by immunological
ignorance alone. A major goal of cancer immunotherapy is to generate an
anti-tumor immune response, e.g., by vaccination with cancer cells fused
with APC or by transfer of anti-tumor T cells. However, many of these
approaches do not efficiently stimulate immunity, or the tumors continue to
grow despite the presence of an immune reaction. Multiple mechanisms
have been identified that tumors use to escape from rejection . It is likely
that malignant escape variants are selected by the immune system. One
strategy to escape from the adaptive immune response is by impaired
antigen presentation. In general, defects in antigen presentation are more
pronounced in metastatic lesions than in the primary tumor. In some
tumors, expression of the tumor antigen is down-regulated, leading to
enhanced tumor incidence and metastasis . Moreover, mutations of the
antigen can result in escape from the initial response and contribute to the
heterogeneity of tumor lesions . The heterogeneous expression of multiple
antigens may hinder the establishment of an efficient specific immune
response. In addition, reduced MHC-I expression prevents recognition of
tumor cells by the immune system . Tumors frequently have a
heterogeneous pattern of MHC-I expression. Total loss of MHC-I is mainly
caused by mutations of the 2 microglobulin subunit . Gene deletions or
rearrangements, point mutations, and defects in transcriptional regulation
lead to selective loss of an MHC haplotype, locus, or allele . Total MHC-I
down-regulation may target the tumor for NK cell attack. Therefore, the
tumor needs further mechanisms to resist NK cell-mediated lysis, such as
the expression of MHC-I surrogates . Reduced presentation of the tumor
antigen is also achieved by defects in the antigen processing machinery.
Down-regulation of the proteasome subunits LMP2 (low molecular mass
polypeptide 2) and LMP7 changes the spectrum of peptides presented by
MHC molecules . Two proteins involved in loading antigenic peptides onto
MHC-I molecules, TAP (transporter associated with antigen processing)
and tapasin, are also frequently mutated or down-regulated in tumor cells, .
TAP deficiency results in loss of MHC-I expression and an increase in
tumorigenesis. Moreover, some proteins of tumorigenic viruses are not
efficiently presented because they interfere with their proteosomal
proteolysis, e.g., by mutation of the clevage site [51]. Another strategy that
tumors use to escape from immune-mediated rejection is the expression of
immunosuppressive factors . These factors may be expressed by the
malignant cells themselves or by non-cancerous cells present at the tumor
site, such as immune, epithelial, or stromal cells. The most prominent of
these factors is transforming growth factor (TGF-). TGF- is a cytokine that
affects proliferation, activation, and differentiation of cells of innate and
adaptive immunity and thus inhibits the anti-tumor immune response.
Moreover, vascular endothelial growth factor (VEGF) is produced by many
tumor cells . Besides its angiogenic properties, it inhibits the differentiation
of progenitors into dendritic cells. Further immunosuppressive factors
expressed by malignant cells are prostaglandins , interleukin (IL)-10 ,
macrophage-colony stimulating factor , and soluble tumor gangliosides .
The membrane protein RCAS1 (receptor-binding cancer antigen expressed
on SiSo cells) inhibits proliferation and induces apoptosis in T cells in vitro,
suggesting a role of this molecule in immune evasion of tumors . The lack
of a T cell response against tumor-associated antigens that are also
expressed by other cells of the body or during development may be
explained by tolerance . In healthy organisms, self-reactive T cells are
tolerized mainly by deletion in the thymus, a process known as central
tolerance. The mechanisms of peripheral tolerance induction prevent
autoimmunity by tolerizing T cells that have escaped the process of central
tolerance. Peripheral tolerance induction is a complex multistep process ,
but in principle, four major mechanisms can be distinguished. One
mechanism is the induction of anergy. T cell activation requires two signals,
binding of a peptide-MHC complex to the TCR and binding of costimulatory
molecules (e.g., B7) to their ligands (CD28) on the T cell surface . If a T cell
binds via its TCR to a peptide-MHC complex on the target cell without
sufficient costimulation, the T cell is rendered anergic and does not become
activated when restimulated with antigen. Many tumor cells do not express
costimulatory molecules and thus may induce anergy in anti-tumor
lymphocytes . Another process of tolerance induction that tumors exploit is
immune deviation. In this process, the immune response is driven toward a
Th2 humoral response away from a Th1 response required for efficient
tumor rejection by cytotoxic T cells. The mechanism of immune deviation is
not exactly understood, but it may depend on secretion of TGF- and IL-10
or on the presentation of the tumor antigen by B cells to CD4 Th cells .
Tumors can also induce the generation of regulatory T cells . Although the
molecular mechanism is not clear, a subset of CD4 T cells seems to
suppress the response of cytotoxic T cells against tumors in some settings
. A further mechanism to establish peripheral tolerance to selfantigens is T
cell deletion. Repetitive stimulation of T cells with the antigen induces
apoptosis, a process referred to as activation-induced cell death (AICD).
Thus, administration of antigens, such as superantigens, peptides, or
allogeneic cells, or direct restimulation of the TCR by anti-CD3 antibodies
has been shown to induce tolerance by T cell deletion . This process is
mainly mediated via the CD95/CD95L death system. Costimulation via
CD28 can rescue T cells from AICD , implicating another important role for
expression of B7 on tumor cells. Tumors have been shown to induce
tolerance by deleting anti-tumor T cells . AICD, as a result of chronic
stimulation with the tumor antigen may contribute to immune escape, yet
the significance of this process has not directly been shown. Two further
strategies used by tumors to evade rejection by the immune system are
related to apoptosis. First, malignant cells have changes in the expression
of molecules involved in apoptosis signaling, resulting in resistance of the
tumor to the killing mechanisms of the immune system. Second, tumors
may adopt a killing mechanism from cytotoxic immune cells to delete the
attacking anti-tumor lymphocytes, a concept called tumor counterattack.
These apoptosis-related immune-escape mechanisms will be discussed in
detail below.
Tumor Immune Escape Mechanisms
Ignorance
Mechanism
Lack of danger signals Lack of tumor antigens in lymphoid organs Growth
in immune privileged sites Lack of adhesion molecules Physical barrier by
stroma.
Impaired antigen presentation

Mechanism
Mutation or downregulation of tumor antigens Mutation or downregulation
of MHC genes Defects in antigen processing (e.g., TAP, LMP deficiency)
Expression of immunosuppressive factors and molecules

Mechanism
Cytokines (TGF-, IL-10, VEGF, etc.) Prostaglandines RCAS1
Tolerance induction
Mechanism
Anergy induction (lack of costimulatory molecules) Immune deviation
Regulatory T cells T cell deletion
Apoptosis
resistance
Mechanism
Expression of anti-apoptotic molecules Downregulation and mutation of
pro-apoptotic molecules Counterattack (?) CD95L expression Expression
of other death-receptor ligands

Modulation Mine Docoment

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antigenic modulation

Loss of detectable antigen from the surface of a cell after incubation

TUMOR IMMUNE ESCAPE MECHANISMS

Tumor Immune Escape Mechanisms

Impaired antigen presentation

Expression of immunosuppressive factors and molecules

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