antigenic modulation

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

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

defects in antigen presentation are more pronounced in metastatic lesions than in the primary tumor. the tumor needs further mechanisms to resist NK cell-mediated lysis. The most prominent of these factors is transforming growth factor (TGF-). are also frequently mutated or down-regulated in tumor cells​. Reduced presentation of the tumor antigen is also achieved by defects in the antigen processing machinery. Total MHC-I down-regulation may target the tumor for NK cell attack. Therefore. such as the expression of MHC-I surrogates . Two proteins involved in loading antigenic peptides onto MHC-I molecules. Moreover. epithelial. TAP deficiency results in​ ​loss of MHC-I expression and an increase in tumorigenesis. reduced MHC-I expression prevents recognition of tumor cells by the immune system . In some tumors. Another strategy that tumors use to escape from immune-mediated rejection is the expression of immunosuppressive factors . point mutations. These factors may be expressed by the malignant cells themselves or by non-cancerous cells present at the tumor site. Down-regulation of the proteasome subunits LMP2 (low molecular mass polypeptide 2) and LMP7 changes the spectrum of peptides presented by MHC molecules . TGF. or allele . by mutation of the clevage site [51].is a cytokine that . In general. expression of the tumor antigen is down-regulated. In addition. e. Tumors frequently have a heterogeneous pattern of MHC-I expression. Gene deletions or rearrangements. mutations of the antigen can result in escape from the initial response and contribute to the heterogeneity of tumor lesions . or stromal cells. Total loss of MHC-I is mainly caused by mutations of the 2 microglobulin subunit . and defects in transcriptional regulation lead to selective loss of an MHC haplotype. . TAP (transporter associated with antigen processing) and tapasin. One strategy to escape from the adaptive immune response is by impaired antigen presentation. such as immune. locus.g. Moreover. some proteins of tumorigenic viruses are not efficiently presented because they interfere with their proteosomal proteolysis. The heterogeneous expression of multiple antigens may hinder the establishment of an efficient specific immune response..that malignant escape variants are selected by the immune system. leading to enhanced tumor incidence and metastasis .

a process known as central tolerance. Although the molecular mechanism is not clear. macrophage-colony stimulating factor . suggesting a role of this molecule in immune evasion of tumors . the immune response is driven toward a Th2 humoral response away from a Th1 response required for efficient tumor rejection by cytotoxic T cells.. Another process of tolerance induction that tumors exploit is immune deviation. four major mechanisms can be distinguished. Further immunosuppressive factors expressed by malignant cells are prostaglandins . If a T cell binds via its TCR to a peptide-MHC complex on the target cell without sufficient costimulation. Tumors can also induce the generation of regulatory T cells . Moreover. and differentiation of cells of innate and adaptive immunity and thus inhibits the anti-tumor immune response. The mechanisms of peripheral tolerance induction prevent autoimmunity by tolerizing T cells that have escaped the process of central tolerance. and soluble tumor gangliosides .g. vascular endothelial growth factor (VEGF) is produced by many tumor cells . the T cell is rendered anergic and does not become activated when restimulated with antigen. interleukin (IL)-10 .affects proliferation. self-reactive T cells are tolerized mainly by deletion in the thymus. Peripheral tolerance induction is a complex multistep process . T cell activation requires two signals. but it may depend on secretion of TGF. One mechanism is the induction of anergy. binding of a peptide-MHC complex to the TCR and binding of costimulatory molecules (e. Many tumor cells do not express costimulatory molecules and thus may induce anergy in anti-tumor lymphocytes . In this process. In healthy organisms. The mechanism of immune deviation is not exactly understood. it inhibits the differentiation of progenitors into dendritic cells. but in principle. B7) to their ligands (CD28) on the T cell surface . 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 . activation.and IL-10 or on the presentation of the tumor antigen by B cells to CD4 Th cells . a subset of CD4 T cells seems to . Besides its angiogenic properties. The membrane protein RCAS1 (receptor-binding cancer antigen expressed on SiSo cells) inhibits proliferation and induces apoptosis in T cells in vitro.

or allogeneic cells. Repetitive stimulation of T cells with the antigen induces apoptosis. malignant cells have changes in the expression of molecules involved in apoptosis signaling. yet the significance of this process has not directly been shown. resulting in resistance of the tumor to the killing mechanisms of the immune system. Second. a process referred to as activation-induced cell death (AICD). First. implicating another important role for expression of B7 on tumor cells. Thus. Two further strategies used by tumors to evade rejection by the immune system are related to apoptosis. Costimulation via CD28 can rescue T cells from AICD . or direct restimulation of the TCR by anti-CD3 antibodies has been shown to induce tolerance by T cell deletion . as a result of chronic stimulation with the tumor antigen may contribute to immune escape. such as superantigens. AICD. Tumor Immune Escape Mechanisms Ignorance Mechanism . This process is mainly mediated via the CD95/CD95L death system.suppress the response of cytotoxic T cells against tumors in some settings . Tumors have been shown to induce tolerance by deleting anti-tumor T cells . administration of antigens. peptides. 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. A further mechanism to establish peripheral tolerance to selfantigens is T cell deletion.

Lack of danger signals Lack of tumor antigens in lymphoid organs Growth in immune privileged sites Lack of adhesion molecules Physical barrier by stroma. LMP deficiency) Expression of immunosuppressive factors and molecules Mechanism Cytokines (TGF-. VEGF.g. TAP.. etc. Impaired antigen presentation Mechanism Mutation or downregulation of tumor antigens Mutation or downregulation of MHC genes Defects in antigen processing (e.) 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 . IL-10.