Essential Components Of An Effective Taspecific T Cellbased Immune Response

Although mechanisms of tumor-specific immunity and its role in the development and progression of cancer in man have been much debated, newer evidence suggest that the components necessary for mounting the anti-tumor immune response are present in cancer patients.

2.1 Tumor antigens

Tumor-antigens. Both the SEREX, T-cell-based and reverse immunology approaches have identified a variety of tumor antigens (TA), which can be broadly classified as tumor antigens that are capable of being recognized by the immunocompetent host: (a) cancer-germ line antigens such as MAGE 1 or 3, BAGE, GAGE and many others that are silent in normal tissues, with the exception of germ cells in the testes and ovaries but expressed in a variety of histologically distinct tumors (3-5); (b) differentiation-specific antigens exemplified by melanoma- and melanocyte-associated tyrosinase, MART-1/Melan-A or gp100 (3-5); and (c) unique antigens generated by point mutations in ubiquitously expressed genes, which regulate key cellular functions, such as MUM-1, CDK4, FLICE or b-catenin (3-5); (d) overexpressed antigens, such as p53, MDM2, CEA, which are components of normal cells but in tumor cells are greatly increased in expression (35,25). Despite the fact that the majority of the known TA, with the exception of mutation products, represent self epitopes and reactive T cells undergo normal thymus selection, the presence of both tumor-specific antibodies and T cells has been clearly documented in tumor-bearing humans and mice (35). Using tetramers, it has been recently possible to identify T cells specific for melanoma differentiation peptides, wild-type p53 peptides and others in the circulation of normal donors and patients with cancer (26,27).

2.2 Antigen presenting cells (APC)

Most of the immunization strategies, which have or are being tested in clinical trials today, share the common goal of inducing TA-specific CTL capable of lysing malignant cells. However, it should be stressed that TA-specific (CD8+) CTL and helper (CD4+) T cells as well as antibody-secreting B cells are essential for anti-tumor effector functions (5,7-10). Moreover, as in most chronic diseases, both non-specific and specific components of the host immune response play a role in the control of tumor growth and metastasis, with some components, e.g., natural killer (NK) cells, polymorphonuclear cells (PMN) and macrophages, thought to participate in the early phase of the response, prior to the appearance of T or B cells. It is noteworthy that NK cells are likely to play a role in the elimination of tumor cells which fail to express major histocompatibility complex (MHC) molecules and thus are not recognized by TA-specific CTL (28).

The structural basis of tumor cell recognition by CTL occurs through the interaction of T cell receptor (TCR) with class I Human Leukocyte Antigens (HLA) complexed to TA-derived peptides (i.e., HLA class I-TA peptide complexes) generated by the antigen processing machinery (APM) (Figure

1) (29). These complexes can be presented to T cells directly by tumor cells through a process defined as direct priming, although the tumor cell is no longer considered as the central antigen-presenting component of an ongoing TA-specific immune response. Alternatively, TA can be captured by professional antigen presenting cells (APC) and processed for indirect priming of CTL via T helper cells. Tumor cells can also transfer TA to APCs via apoptotic or necrotic tumor cells as well as tumor-derived exosomes. TA-derived peptides are then presented to T cells through a process defined as cross priming (30). Heat shock proteins (HSP) can also transfer TA to APC by chaperoning TA-derived peptides which are eventually loaded onto HLA class I antigens and presented to CTL (31).

Figure 1. Generation and interaction of HLA class I antigen-antigen derived peptide complexes with T cells and NK cells. (A) Intracellular protein antigens, which are mostly endogenous, are marked for ubiquitination within the cytosol and subsequently degraded into peptides by the proteasome. Peptides are then transported into the ER through TAP. (B) Nascent, HLA class I antigen heavy chains are synthesized in the ER and associate with the chaperone immunoglobulin heavy chain binding protein (BiP), a universal ER chaperone involved in the translation and insertion of proteins into the ER. Following insertion into the ER, the HLA class I heavy chain associates with the chaperone calnexin and the thiol-dependent reductase ERp57. Calnexin dissociation is followed by HLA class I heavy chain association with P2m, tapasin and the chaperone calreticulin. Calnexin, calreticulin and ERp57 play a role in folding of the HLA class I heavy chain. Tapasin brings the HLA class I heavy chain-P2m-chaperone complex into association with TAP and plays a role in both quantitative and qualitative peptide selection. (C) The trimeric HLA class I heavy chain P2m peptide complex is then transported to the plasma membrane where it plays a major role in the interactions between target cells and activation of peptide-specific CTL through TCR or with NK cells through killer inhibitory receptors (KIR).

Dendritic cells (DC) are the most potent APC. DC have a high surface density of HLA antigens and costimulatory molecules and can produce immunostimulatory cytokines and chemokines (32). Furthermore, DC are efficient in processing exogenous TA via the HLA class I antigen pathway, cross-presenting TA to CD8+ T cells and also interact with cells of the innate immune system, i.e., NK and NKT cells (33-36). After internalizing TA at the tumor site, chemokine receptor 7-positive (CCR7+) DC traffic to the tumor-draining lymph nodes, where they interact and influence the maturation of T cells within the paracortical cords and of Ab-producing plasma cells in the medullary cortex (32,38). DC may also be present at the tumor site and are referred to as tumor-associated DC (TADC). TADC cross-present TA to recruited CD8+ T cells, potentially inducing their activation, proliferation and maturation into TA-specific effector cells. In addition, TADC, when appropriately activated, mediate the sensitization of naïve T cells that may have been recruited into the tumor site. Thus, interactions between the tumor-infiltrating T lymphocytes (TIL) and TADC are essential for driving and maintaining the local TA-specific immune response. Optimal biologic functions and survival of T cells and DC may be enhanced by reciprocal signaling between these two cell types via HLA class I-peptide complexes and co-stimulatory receptor-ligand pairs (39).

Interaction of TCRs with HLA class I antigen-peptide complexes, together with help from activated CD4+ T cells, leads to activation and clonal expansion of TA-specific CD8+ CTL. Based on our current understanding, both CD8+ and CD4+ T lymphocytes can be categorized into at least three functional subsets, depending on the cytokines they produce (40-42). These subsets include i) Tc1/Th1 (Type-1) cells which produce IFN-y and IL-2; ii) Tc2/Th2 (Type-2) cells which produce IL-4 and IL-5, and iii) Th3/T regulatory (T-reg) cells which produce IL-10 and/or TGF-p. It is worth noting that Type-1-biased immune responses are strongly supported by IL-12p70 (43) and are associated with the host's ability to control and eliminate intra-cellular pathogens and tumors. On the other hand, Type-2-biased immune responses inhibit Type-1 responses and do not favor the development of cellular tumor immunity. Once TA-specific T cells are activated, they leave the lymph node environment and make their way via the lymphatics to tumor site(s), arriving as primed, but not necessarily fully differentiated effector cells. CTL are expected to induce programmed cell death of malignant cells which express targeted HLA class I antigen-peptide complexes, through the perforin-granzyme mechanism and/or the Fas/Fas ligand pathway (44). The latter requires the expression of Fas receptor on target cells and Fas ligand on effector CTL.

2.3 Cytokine milieu

Through secreted chemokines and cytokines, tumors can induce and amplify non-HLA-restricted, inflammatory responses in the host, leading to the accumulation of immune cells at the tumor site. Moreover, cytokines and chemokines play a key role in shaping functional attributes of both T cells and DC in a tissue microenvironment. Like T cells, DC are functionally heterogeneous and the polarization of DC into distinct subsets, i.e. DC1, DC2 and DC3, appears to correspond to the functional T cell subsets they interact with, i.e. Type-1, Type-2 and T-reg (38,40). For example, DC matured in the presence of Th1 type cytokines such as IFN-y are polarized to secrete IL-12p70, a cytokine which promotes Thl-type responses (DC1); DC matured in the presence of the Th2 type cytokines such as IL-4 and IL-5 are polarized to promote Th2-type responses (DC2), and DC matured in the presence of regulatory T cell (T-reg) cytokines such as IL-10 and TGF-P, might assume a down-regulatory activity (DC3). The context of DC polarization and their ability to "switch" their functional potential in response to a new cytokine cocktail are being extensively studied at present, and both in vitro and in vivo experiments indicate a remarkable plasticity of this cellular population, which is clearly driven by cytokines and chemokines (45,46). Overall, it is clear that cytokines dictate the nature of the locoregional immune response, depending on the activation signals received by the T cells and DC infiltrating the tumor microenvironment (47).

Clearly a number of components are necessary for the generation and maintenance of an effective TA-specific T cell-based immune response including TA, APC, immune effectors and cytokines. The role each of the components plays in the development of TA-specific T cell-based immune responses as well as the cellular interactions envisioned to take place within the tumor microenvironment are summarized in Figure 2.

Tumor Microenvironment Immune Response

Figure 2. Schematic representation of the cellular interactions that may occur within the tumor microenvironment. Immune escape mechanisms utilized by tumor cells include secretion of immunoinhibitory factors (blue rectangles) and cytokines (e.g., IL-10, TGF-P) produced by the tumor (Red circles); and/or loss of TA (Green triangles). Together, these effects promote a tumor microenvironment suppressive for immune cells (DC, Tc, Th) and enriched in regulatory T cells (T reg).

Figure 2. Schematic representation of the cellular interactions that may occur within the tumor microenvironment. Immune escape mechanisms utilized by tumor cells include secretion of immunoinhibitory factors (blue rectangles) and cytokines (e.g., IL-10, TGF-P) produced by the tumor (Red circles); and/or loss of TA (Green triangles). Together, these effects promote a tumor microenvironment suppressive for immune cells (DC, Tc, Th) and enriched in regulatory T cells (T reg).

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