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ANTIGEN PRESENTATION IN TUMOR IMMUNITY

MARIA-DANIELA CIOACĂ, ŞTEFANA-MARIA PETRESCU

Institute of Biochemistry of the Romanian Academy, Splaiul Independenţei 296, 060031 Bucharest, Romania

(Received October 7, 2007)

One of the most fascinating works of our present is the understanding of molecular mechanisms underlying processing and presentation of antigens. Knowledge of the mechanisms of initiation and propagation of immune responses provides a good basis for development of tumor immunotherapy that uses specific antibodies, cytokines or immunocompetent cells. This review describes some aspects of antigen processing and presentation in normal and transformed cells.

Key words: MHC-I, MHC-II, antigen presentation, tumor immunity, tumor-immune evasion.

INTRODUCTION

Tumor cells distinguish from their normal counterparts in that they lose the functional and phenotypic characteristics of the tissue from which they are derived. They express a wide variety of tumor antigens including both tumor-specific antigens, that are unique to cancer cells, and tumor-associated antigens, which occur also on some normal cells but are found at much higher density on cancer cells (1). The transformation of a normal cell to malignancy can result from different causes: it may occur spontaneously by random mutations or gene rearrangements, or it may be induced by a chemical, physical, or viral carcinogen. Immune responses against tumor antigens bear both similarities and differences to immune responses against self tissue antigens, tumor etiology greatly influencing the immunogenicity of a tumor-specific antigen (2). For example, virus-induced tumor antigens are strong immunogens, and skin cancers induced by UV light are much more immunogenic than tumors induced by chemicals. Although the antitumor cell-mediated immune response may control or limit the growth of human tumors, a poor or ineffective immune response can occur with particular tumors, due to their capability to avoid detection or destruction by the immune system.

ANTIGEN PRESENTATION BY MHC PATHWAYS

Processing and presentation of endogenous or exogenous proteins that are recognized as antigens by an immune system can be acquired by three distinct pathways: the MHC class I, the MHC class II and cross-presentation (3).

ROM. J. BIOCHEM., 45, 2, 183–195 (2008)

Maria-Daniela Cioacă, Ştefana-Maria Petrescu 2

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THE MHC CLASS I-PRESENTING PATHWAY

The major histocompatibility complex class I (MHC-I) antigen presentation pathway is constitutively activated in all nucleated cells. Almost all cells are able to process endogenous/intracellular antigens, to transport MHC-I–peptide complexes to the cell surface and to present them to CD8+ T lymphocytes (Figure 1). The recognition of MHC-I–antigenic peptide complexes by CD8+ T cells triggers cytotoxic activity and leads to apoptosis or lysis of malignant or infected cells.

Fig. 1. – Antigen-processing by MHC-I pathway.

Processing of endogenous antigens requires translocation of the polypeptide chains into the cytosol, proteasomal degradation, transport of the antigenic peptides into the endoplasmic reticulum (ER), assembly of MHC-I–peptide complexes and transport of the complexes to the cell surface, via the Golgi apparatus (4).

Transfer of polypeptide chains from the ER to the cytosol is mediated by Sec 61 complex. Substrates exposed to the cytosol are processed further by ER associated components of the ubiquitin conjugated machinery. Proteasomal targeting is mediated and assisted by ubiquitin, a protein with low molecular weight (78 amino acids) that is covalently attached by its carboxy terminus to the ε-amino group of selected lysin residues of the substrate protein. The proteasome

3 Tumor antigen presentation

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contains a catalytic core subunit, which is a 20S (700 kDa) cylindrical particle composed of 28 subunits arranged as four heptameric rings. The two outer rings are made up of α-subunits and the two inner rings are composed of β-subunits. The α-subunits have structural and regulatory functions, while the β-subunits have catalytic functions. The proteasome produces peptides with a size distribution of 3–30 amino acid residues, with an optimum of 6–11 residues (5, 6). Peptides generated by the proteasome are translocated from the cytosol into the lumen of the ER by transporter associated with antigen processing (TAP). Deletion or mutation of TAP severely affects the translocation of peptides into the ER (7). TAP protein delivers peptides to the ER, but it is also involved in the formation of a large loading complex, critical for maturation of the MHC-I–peptide complex.

The macromolecular loading complex contains the MHC I molecule, associated with the chaperone calreticulin and the thiol reductase ERp57, tapasin and TAP. MHC-I molecules are heterodimers composed of two polypeptidic chains: a long α-chain and a short β-chain called β2-microglobulin. The α-chain contains three domains: α1, α2 and α3. The antigen-binding region is formed by α1 and α2-domains and consists in a groove that will accommodate the antigenic peptide. The α3-domain binds the CD8 molecule present on the surface of cytotoxic T cell. The transmembrane domain of MHC-I molecule is composed of hydrophobic amino acids, and the cytoplasmic region contains the phosphorylation sites and the sites for cytoskeletal proteins binding. The MHC-I molecules interact with the TAP by an ER-resident type I glycoprotein named tapasin (TAP-associated glycoprotein). The chaperone calnexin and the ERp57 bind to the TAP-tapasin complex and generate an intermediate which is capable of binding to the MHC-I molecule. The formation of this macromolecular complex is accompanied by loss of calnexin and binding of calreticulin (8–10). Tapasin is a member of the immunoglobulin superfamily and mediates formation of the complex and the cross-talk of structural information between MHC-I and TAP molecules. Tapasin has two independent functions: it increases the level of TAP, thereby increasing the efficiency of peptide transport, and it associates with MHC-I molecules, thereby facilitating the direct loading and assembly of MHC-I molecules. MHC-I-antigenic peptide complexes are then exported from the ER and transported to the plasma membrane through the Golgi apparatus.

Abnormalities of MHC Class I Pathway in Tumor Cells

Down-regulation of the antigen presentation machinery, particularly the MHC-I pathway, is considered as the most common strategy used by tumor cells to evade immune control (11). Experimental data have proved that antigen processing and presentation are highly affected in cellular lines that show down-regulation of TAP protein, tapasin, or some immunoproteasome subunits. Usually, transfection


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of affected cells with wild-type proteins leads to defect correction and to a proper processing of antigens.

Downregulation of tumor antigens due to a low level of the TAP protein was evidenced for many tumor cells. An important fraction of these cells can secrete IL-10, a cytokine that is known to lower TAP expression. The presence of a point mutation that affects TAP gene can be another cause of TAP downregulation. Chen et al. identified a mutation that introduced a stop codon in TAP gene, leading to the expression of a truncated, biologically inactive protein. Tumor cells that present downregulation of TAP protein fail to be recognized by cytotoxic T lymphocytes. Downregulation of TAP also determines a low expression of MHC-I molecules. This defect can be sometimes corrected by addition of interferon-γ (IFN-γ) to the extracellular medium of cultured cells. Complete absence of MHC-I expression caused by mutations of the β2-microglobulin gene is frequently exhibited by tumor cells (12, 13).

Another modification occurring in transformed cells, which can affect their detection and recognition by the immune system is downregulation of some immunoproteasome subunits such as LMP2 and LMP7. This phenomenon is associated with very low chemotrypsin-like and trypsin-like activities and, as a consequence, with an inefficient processing of tumor antigens. LMP7 down-regulation is associated in melanoma cells with a low expression of the TAP protein. Still, the altered expression of the LMP subunit could not be associated with the clinical progression of the disease, so far. But experimental data have proved that it has a negative effect on antigen presentation to CD8+ T cells (14).

THE MHC CLASS II-PRESENTING PATHWAY

The constitutive expression of major histocompatibility complex class II (MHC-II) molecules is limited to “professional” antigen-presenting cells (APCs) that include B cells, monocytes, macrophages and dendritic cells. MHC-II expression can be induced on other cell types by IFN-γ treatment. Exogenous/ extracellular antigens (proteins derived from exogenous sources and antigenic proteins originating from cells or cellular remains) are processed in the endocytic compartments of the APCs and are presented by MHC-II molecules to the CD4+ T cells (15) (Figure 2). Genarally, tumor cells express class I rather than class II molecules.

MHC-II molecules are composed of an α-chain and β-chain, which are assembled in the ER. Here, three MHC-II heterodimers bind a trimer of the invariant chain (Ii), which is a type II glycoprotein, and form a nanomeric complex that will be exported to the Golgi apparatus and further to the endocytic vesicles. The Ii chain is proteolytically degraded by aspartic and cysteine proteases and the resulted Ii-derived peptide (CLIP) associates with MHC-II molecules and forms the MHC-II–CLIP complexes (16). They accumulate in a prelysosomal compartment designated as “MHC-II-loading compartment”, where the antigenic peptide is exchanged for CLIP.


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Fig. 2. – Antigen-processing by MHC-II pathway.

The exchange process is assisted by HLA-DM and HLA-DO molecules (17, 18). HLA-DM protein facilitates CLIP dissociation and stabilizes the MHC-II molecule during the exchange phase. It acts as a “peptide editor”, favoring the dissociation of any class-II-bound peptide, thus ensuring that peptides binding weakly can be replaced by peptides binding more tightly. HLA-DO protein modulates the HLA-DM activity. Then, the MHC-II–antigenic peptide complexes are released to the APC surface and are displayed in order to be recognized by CD+ T cells.

The Ii protein has important roles: maintains the tertiary structure of MHC-II molecules, which are instable at the neutral pH within the ER, prevents premature binding of the antigenic peptides to MHC-II molecules in the ER or Golgi apparatus and controls sorting of MHC-II molecules to the endocytic vesicles by a dileucine-type sorting signal in its cytoplasmic domain.


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The low pH in the endosomal compartments is essential for activation of proteases that cleave the antigens, for Ii protein processing and for providing an optimal environment for CLIP dissociation and peptide binding to MHC-II molecules (19).

Abnormalities of MHC Class II Pathway in Tumor Cells

Many types of normal cells do not express MHC-II molecules and are not capable of presenting exogenous antigens to the CD4+ T cells. Tumor cells frequently present antigens in the context of MHC-II molecules. In these cells, down-regulation or lack of expression of HLA-DM (H2-M in mouse) or MHC II proteins, and sometimes up-regulation of Ii protein can occur. All these alterations will eventually lead to the inefficiency of the immune-mediated defense of the organism.

Ii protein is the restricting factor for antigenic peptide presentation and therefore the level of expression of this protein will determine activation and proliferation of T cells. In Hodgkin’s disease, a lymphoproliferative disorder tumor cells display on their surface an important fraction of MHC-II molecules in complexes with CLIP peptide. This abnormality is the consequence of an alteration in the MHC-II presenting pathway and constitutes a mechanism by which tumor cells avoid recognition by immune system (20).

Professional Antigen-Presenting Cells

APCs are cells of the immune system responsible for processing and presentation of antigens to the T cells. “Professional” APCs naturally express MHC-I and MHC-II molecules and also accessory/costimulatory molecules (CD40, B7) that generate a costimulatory signal which stabilizes the interaction between APC and T cell. Expression of MHC-II molecules on the surface of these cells is increased after activation or upon maturation. In humans there are three different types of “professional” APCs: dendritic cells, macrophages and B lymphocytes. Differently, the “amateur” or “nonprofessional” APCs present MHC-II molecules on their surface only upon activation by the antigen. “Amateur” APCs do not express costimulatory molecules, being recognized only by activated T cells or T cell hybridomas (21). Tumor antigens released from dead tumor cells are presented by “professional” APCs.

Dendritic cells (DCs) are the most potent professional APCs and are essential for development of specific immune responses against tumors. They have different anatomical locations, phenotypes and functions. DCs control the quality of the immune response, activate T, NK and NKT cells and produce cytokines (22, 23).

DCs present two consecutive functional states: immature and mature. Immature DCs reside in peripheral tissues and have a great capacity to ingest antigens from the extracellular medium by phagocytosis and receptor-mediated


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endocytosis (particulate antigens) or by pinocytosis (soluble antigens). They have most of their MHC-II molecules concentrated in the endocytic pathway, displaying a low level of MHC-II molecules at plasma membrane. After encountering antigens, immature DCs undergo differentiation and maturation. Mature DCs migrate to secondary lymphoid organs where they present the processed antigens to naive T cells, in the context of MHC molecules, and induce antigen-specific immune responses. In contrast to immature DCs, mature cells have a low capacity to ingest foreign molecules and a great capacity to stimulate T cells due to upregulation of surface expression of MHC-II molecules (24, 25).

The CD4+ T (T helper or Th) cells secrete cytokines which activate other effector cells, e.g., cytotoxic T cells and B cells, promoting the immune responses. The immune response efficiency is determined by the balance between Th1 and Th2 subtypes of the Th cells, the subtype differentiation depending on cytokines they secrete (26). DCs can modulate the Th cell response: DC1 subset promotes differentiation of pre-Th1 cells in Th1 cells, while DC2 subset induces a Th2 response.

Macrophages result from monocytes by differentiation in different tissues. They are very efficient in eliminating diverse aggressors. Macrophages take up antigens by phagocytosis, become activated and secrete high quantities of cytokines. After processing the phagocytosed antigens, macrophages will expose MHC-II–antigenic peptide complexes at their surface in order to be recognized by CD4+ T cells.

Macrophages have two main roles to play in tumor immunity: antigen presentation to initiate a specific immune response, and direct cytolysis of the tumor cells following activation by IFNγ, TNF and IL-4 produced by antigen-stimulated Th cells.

B lymphocytes interaction with an antigen is mediated by membrane immuno-globulins. Binding of an antigen to immunoglobulin M molecules (B cell receptor) will determine stimulation of B cells and up-regulation of a set of membrane proteins (MHC-II, B7), increasing thus the capacity of B cells to serve as APCs. After antigenic stimulation, B cells express cytokine receptors that will induce cell proliferation and differentiation into plasma and memory B cells. B cells can function as APCs at very low levels of the presenting antigen, by comparison with other APCs (100–1000 times lower), due to the very specific binding of the antigens by immunoglobulin receptors (27, 28).

CROSS-PRESENTATION

Cross-presentation is a process by which antigenic peptides derived from exogenous/extracellular antigens are presented in complexes with MHC-I molecules to CD8+ T cells. Cross-presentation can be a TAP dependent or independent process, depending on the mechanism of antigen processing and loading onto MHC-I


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molecules (29, 30). Two mechanisms are suggested to explain the cross-presentation events. According to the first mechanism, the antigens are processed and assembled with MHC molecules in specialized compartments that result from fusion of phagosomes with ER and that contain specific proteins like Sec61, TAP, tapasin, calnexin, ERp57 and calreticulin. The endocytosed polypeptidic chains are translocated into the cytoplasm and are degraded by the proteasomal pathway. Import of the antigenic peptides is mediated by TAP transporter and specific molecular chaperones will promote assembly of antigenic peptides with MHC-I molecules. Then, the mixed ER–phagosome compartments are recruited to plasma membrane and MHC-I–antigenic peptide complexes will be displayed in order to be recognized by CD4+ T cells (31). The second mechanism assumes that assembly of MHC-I–antigenic peptide complexes occurs in the post-Golgi compartments and endolysosomes. Experimental studies revealed that MHC-I dimmers contained a signal sequence for endosomal sorting in their cytoplasmic domain.

Particularly dendritic cells, but also macrophages and B lymphocytes are capable of cross-presentation. APCs recruited by tumor cells process tumor antigens and present them in the context of MHC-I and MHC-II molecules to CD8+ and respectively CD4+ T cells from lymph nodes. Cross presentation is necessary for induction of a vigorous immune response against most tumors and is required in tumor vaccination, to induce cytotoxic immunity.

IMMUNOLOGICAL SYNAPSE

Immunological synapse is a specialized cell–cell junction between a T cell and an APC. Synapse formation requires participation of adhesion molecules, actin cytoskeleton and signaling through the T-cell receptor (TCR). At the cell–cell contact site, cell surface proteins and secreted proteins reach a very high concentration. Initiation and propagation of TCR signaling pathway occurs within special microregions of the plasma membrane called lipid rafts. TCR is a dimeric, cell surface glycoprotein belonging to immunoglobulin family and that confers antigen specificity to T cells. Its α and β chains consist each of two extracellular domains, one constant and one variable, with a joining segment in between. Within the variable domain, at least three hypervariable regions, directly involved in antigen binding, have been identified. A small population of T cells has TCR composed of a γ and a δ chain. The γδ TCR specificity differs from that of αβ TCR. It may recognise antigens associated with non-classical MHC molecules. TCR associates with CD3 complex. The complex contains six polypeptidic chains (the γε, δε and ζζ dimers) and is required for cell surface expression of the TCR and for signal transduction into the T cell when TCR recognizes MHC–peptide complexes. Interaction of a T cell with an antigen initiates a biochemical cascade within the T cell that induces proliferation and differentiation of T cells into effector and memory


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T cells (32–34). Some accessory and costimulatory molecules engage following interaction between TCR and MHC–peptide complex to activate the T cell.

The accessory molecules CD4 (on CD4+ T cells) or CD (on CD8+ T cells), leukocyte function-associated antigen (LFA)-1 and LFA-2 (CD2), expressed on T cells, attach noncovalently to ligands MHC-II or MHC-I, intercellular adhesion molecule (ICAM) and LFA-3 respectively, present on APCs, increasing thus adhesion between T cell and APC. The TCR-mediated signal is followed by a costimulatory signal resulting from the interaction between CD28 on the T cells and CD80 (B7-1) or CD86 (B7-2) on the APCs. This signal induces lymphokine production and upregulation of other accessory/costimulatory molecules (35). The alternative interaction between CD80/CD86 and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) stops the costimulatory signal and inhibits the activated T cell. Interruption of this inhibitory pathway by the use of anti-CTLA-4 antibodies appears to be a promising strategy for cancer immunotherapy (36).

COOPERATION BETWEEN CD4+ T CELLS AND CD8+ T CELLS IN ANTI-TUMOR IMMUNE RESPONSE

Most tumor cells do not express MHC-II molecules on their surface and require participation of the CD4+ T cells in the effector phase of the immune response (37). Cooperation between CD4+ T cells and CD8+ T cells in anti-tumor immune responses is now well documented, although the molecular mechanisms involved are not fully elucidated (38) (Figure 3).

Tumors recruit APCs (e.g., DCs) which process and present circulating tumor antigens to CD4+ T cells, in the context of MHC-II molecules. Upon engagement of TCR, the CD40 ligand (CD40L), a member of the TNF family, is expressed on the surface of CD4+ T cells. The interaction between CD40L and its receptor, CD40 (a member of the TNF-receptor family), on the DC surface, induces activation and maturation of DCs. This consists in increased expression of MHC-II, MHC-I, ICAM-1, CD80 and CD86 molecules. DCs activation is essential for initiating a Tc response. Improving CD40 function in vivo, to augment anti-tumor immunity, could be a therapeutic strategy in cance (39). The CD40–CD40L interaction also triggers the production of IL-12 cytokine by DCs (40). This is increased by IFNγ secreted by Th1 cells. In turn, DCs stimulate IFNγ production by Th cells and initiate Th1 profile (41). Full activation of naive CD4+ T cells also requires costimulation through the interaction between the constitutively expressed molecule CD28 and CD80/CD86 on DCs. Following activation, the costimulatory molecule OX40 is expressed on its surface. OX40 interacts with OX40L on the surface of activated DCs, resulting in down-regulation of the CTLA-4 inhibitory molecule and enhancement of both effector and memory responses of CD4+ T cells.


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Fig. 3. – Tumor antigen presentation and cooperation between CD4+ and CD8+ T cells in tumor

immunity.

Experimental studies in murine tumor models have shown that the interaction between OX40 and a soluble OX40L–immunoglobulin fusion protein enhances tumor immunity (42). The following interaction between 4-1BB receptor on activated CD4+ T cells and 4-1BBL on mature and activated DCs has also a costimulatory effect (43) and can be exploited therapeutically (44).

The activated CD4+ T cells became functional Th cells, which express Th1 and Th2 cytokines and recruit antitumor effector cells. Experimental data showed that an efficient anti-tumor citotoxic T cell response correlates with the Th1 subtype of Th cells, the Th1 response being considered to be the most appropriate for tumor immunity. The Th1 cells release the potent T cell growth factor IL-2, which binds to IL-2 receptor on the same Th1 cell allowing cell proliferation. The IL-2 cytokine is also necessary for growth and proliferation of CD8+ T cells. By this help, CD4+ T cells play a major role in generating effector and memory,


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tumor-specific Tc cells. The Th1 cells can activate other tumoricidal cells (macrophages and NK cells) and are inhibited by IL-4 and IL-10 produced by Th2 cells. The Th2 cells activate B cells to proliferate and secrete anti-tumor antibodies and are inhibited by IFNγ secreted by Th1 cells. Th cells may be directly lytic to tumor cells by TNF cytokine they secrete.

It is possible that the inability of the immune system to control tumor growth to be due to an inadequate activation of the tumor-specific Th cells, leading to a poor anti-tumor Tc response.

IMMUNE SYSTEM EVASION BY TUMORS

Besides alteration of components of the antigen-processing and presentation machinery, the tumor cells developed many other mechanisms to evade or overcome the immune response (45, 46):

− secretion of an excess of circulating antigens that inhibit specifically cell-mediated cytotoxicity;

− a lower or loss of expression of a tumor antigen which might be capable to initiate a good immune response (a process called immunoselection);

− internalization and/or secretion of tumor antigens that block specific antibodies away from tumors (a process called antigenic modulation);

− masking of tumor antigens by molecules displayed on tumor cell surface, leading to a good protection of the tumor against the immune attack;

− lack of expression of costimulatory molecules CD80/CD86 on tumor cells, that induces anergy of tumor-specific CD8+ T cells;

− activation of negative costimulatory signals; − expression on the tumor cell surface of molecules that bind receptors on

T, B and NK lymphocytes, inhibiting lymphocyte proliferation and causing apoptosis of the activated lymphocytes;

− secretion by tumor cells of soluble factors (e.g., cytokines and growth factors) which inhibit directly or indirectly the immune response (a process called immunosuppression), rendering a tolerant tumor microenvironment.

An improved understanding of the molecular mechanisms underlying tumor antigen presentation and tumor immune resistance will contribute in the future to improve immunotherapeutic strategies for cancer.

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