STEM CELLS 2006;24:74 -85

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This study focuses on the specific CD4+ T cell requirement for optimal induction of cytotoxicity against MHC class II negative autologous tumors (AuTu) collected from patients with various types of cancer at advanced stages. CD4+ T cells were induced in cultures of cancer patients’ malignant effusion-associated mononuclear cells with irradiated AuTu (mixed lymphocyte tumor cultures (MLTC)) in the presence of recombinant IL-2 and recombinant IL-7. Tumor-specific CD4+ T cells did not directly recognize the AuTu cells, but there was an MHC class II-restricted cross-priming by autologous dendritic cells (DCs), used as APC. CD8+ CTL, also induced during the MLTC, lysed specifically AuTu cells or DCs pulsed with AuTu peptide extracts (acid wash extracts (AWE)) in an MHC class I-restricted manner. Removal of CD4+ T cells or DCs from the MLTC drastically reduced the CD8+ CTL-mediated cytotoxic response against the AuTu. AWE-pulsed DCs preincubated with autologous CD4+ T cells were able, in the absence of CD4+ T cells, to stimulate CD8+ T cells to lyse autologous tumor targets. Such activated CD8+ T cells produced IL-2, IFN-γ, TNF-α, and GM-CSF. The process of the activation of AWE-pulsed DCs by CD4+ T cells could be inhibited with anti-CD40 ligand mAb. Moreover, the role of CD4+ T cells in activating AWE-pulsed DCs was undertaken by anti-CD40 mAb. Our data demonstrate for the first time in patients with metastatic cancer the essential role of CD4+ Th cell-activated DCs for optimal CD8+ T cell-mediated killing of autologous tumors and provide the basis for the design of novel protocols in cellular adoptive immunotherapy of cancer, utilizing synthetic peptides capable of inducing T cell help in vivo.

Objectives: The aim of this study was to document the pattern of immune response, assessed by the measurement of both Th1 and Th2 serum cytokines, in patients suffering from autoimmune thyroid disease and toxic nodular goiter. Methods: Both Th1 and Th2 serum cytokine levels were assayed in patients suffering from Graves’ disease (GD, n = 25), Hashimoto’s thyroiditis (HT, n = 21), and toxic nodular goiter (TNG, n = 7) and compared with corresponding levels of 25 healthy controls. Serum concentrations of IL-2, IL-1β, INF-γ, TNF-α, IL-12, IL-15, IL-10, IL-18, IL-4 and IL-5 were assayed in fasting serum samples. Results: It was found that patients with HT had higher IL-2 serum levels (12.16 ± 0.66 pg/ml) compared to patients with TNG (9.25 ± 0.84 pg/ml), GD (7.86 ± 0.30 pg/ml) and controls (7.36 ± 0.45 pg/ml; p = 0.0001), higher INF-γ levels (7.60 ± 0.33 pg/ml) compared to patients with TNG (5.77 ± 0.55 pg/ml), GD (5.74 ± 0.24 pg/ml) and controls (5.09 ± 0.27 pg/ml; p = 0.0009), higher IL-12 levels (3.57 ± 0.19 pg/ml) compared to patients with TNG (2.57 ± 0.21 pg/ml), GD (2.48 ± 0.13 pg/ml) and controls (2.59 ± 0.23 pg/ml; p = 0.004), and higher IL-18 levels (27.52 ± 1.75 pg/ml) compared to patients with TNG (18.71 ± 2.24 pg/ml), GD (15.44 ± 1.39 pg/ml) and controls (15.16 ± 1.62 pg/ml; p = 0.0002). In contrast, patients with GD had higher serum levels of IL-4 (4.11 ± 0.33 pg/ml) compared to patients with HT (3.0 ± 0.16; p = 0.02) and higher IL-5 levels (4.22 ± 0.30 pg/ml) compared to patients with TNG (3.21 ± 0.58 pg/ml), HT (2.75 ± 0.16 pg/ml) and controls (2.0 ± 0.19 pg/ml; p = 0.0001). Patients had lower IL-1β serum levels (TNG 2.45 ± 0.20, HT 2.52 ± 0.14, GD 2.68 ± 0.12 pg/ml) compared to controls (3.6 ± 0.20 pg/ml; p = 0.008). Conclusions: The above findings suggest that a Th1 pattern of immune response characteristic of cellular immunity is dominant in HT, whereas the predominance of Th2 cytokines in GD indicates a humoral pattern of immune reaction.

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The use of synthetic peptides as vaccines aimed at the induction of therapeutic CD8-positive T-cell responses against tumor cells initially experienced great enthusiasm, mostly because of advances in vaccine technology, including design, synthesis, and delivery. However, despite impressive results in animal models, the application of such vaccines in humans has met with only limited success. The therapeutic activity of vaccine-stimulated, tumor-specific, CD8-positive T cells can be hampered through the physical burden of the tumor, tolerance mechanisms, and local factors within the tumor microenvironment. Recently, accumulating evidence has suggested that combining a peptide-based therapeutic vaccination with conventional chemotherapy can uncover the full potential of the antitumor immune response, increasing the success of immunotherapy. In addition, therapeutic vaccination in the preventive setting has been extremely effective in eliciting antitumor responses in preclinical tumor models and has demonstrated good promise clinically in patients with minimal residual disease. The rationale behind preventive vaccination is that patients with minimal tumor burden still have a fully competent immune system capable of developing robust antitumor responses. Finally, therapeutic CD8-positive T-cell peptide vaccines have been improved by coimmunization with T-helper epitopes expressed on long peptides.

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