Relevance of the Tumor Antigen in the Validation of Three Vaccination Strategies for Melanoma

Bellone, Matteo; Cantarella, Daniela; Castiglioni, Paola; Crosti, Maria Cristina; Ronchetti, Anna; Moro, Monica; Garancini, Maria Paola; Casorati, Giulia

doi:10.4049/jimmunol.165.5.2651

Cited by 119 publications

(100 citation statements)

References 31 publications

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“…The data are presented by combining two independent experiments. Augmenting antitumor immunity by CD11c-Bcl-xl in vivo JH Kim et al activity in syngeneic C57BL/6 mice ( Figure 1a and b, 31,32 ). Foreign tumor antigens fused to hsp70 DNA vaccine have been shown to induce enhanced antitumor immunity in murine tumor models.…”

Section: Discussionmentioning

confidence: 98%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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T-cell priming is strongly affected by the longevity of antigenbearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. 'Survival gene' Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFNg-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that 'survival gene' Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer. Gene Therapy (2005) 12, 1517-1525.

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Section: Discussionmentioning

confidence: 98%

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

et al. 2005

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“…In order to assess the capacity of DC to polarize naive CD8 + T cells towards Tc1 or Tc2 at different activation stages, DC induced from bone marrow precursors [29,30] were exposed to either LPS or TNF-a for different time periods. As previously reported [29], untreated DC (not exposed to maturation stimuli; 0h-DC) showed a heterogeneous expression of MHC class I, MHC class II, CD40, CD80 and CD86 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…When tested in standard cytotoxicity assays, both OT-1 Tc1 and Tc2 populations efficiently killed both RMA cells expressing OVA [30] and RMA cells loaded with the SIINFEKL peptide, but not unpulsed RMA cells (Fig. 5).…”

Section: Phenotype and Functional Characterization Of Tc1 And Tc2 Popmentioning

confidence: 99%

“…Bone-marrow-derived DC cells were obtained from C57BL/6 mice as previously described [29,30]. To induce maturation, DC were exposed to LPS (1 lg/mL), TNF-a (50 ng/mL; R&D Systems) or ODN-1826 (CpG; 5 lg/mL; InvivoGen, San Diego, CA) for 8 or 48 h of culture.…”

Section: Generation and Functional Characterization Of DCmentioning

confidence: 99%

“…4). At least for CD154, this expected result [40] may be due to the absence of brefeldin A in the culture medium [41].When tested in standard cytotoxicity assays, both OT-1 Tc1 and Tc2 populations efficiently killed both RMA cells expressing OVA [30] and RMA cells loaded with the SIINFEKL peptide, but not unpulsed RMA cells (Fig. 5).…”

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confidence: 91%

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Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

Boni¹,

Iezzi

Degl’Innocenti³

et al. 2006

Eur J Immunol

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Dendritic cell (DC) maturation influences the priming and polarization of T lymphocytes. We recently found that early activated DC (i.e. DC exposed to promaturation stimuli for 8 h) were more prone to prime in vivo a type-1 cytotoxic T cell (Tc1) response than DC exposed to pro-maturation stimuli for 48 h (48h-DC). We investigated whether 48h-DC, conversely, allowed the induction of Tc2 cells. Antigenpulsed mouse bone-marrow-derived DC at any maturation stage, in the presence of exogenous IL-12, skewed in vitro naive CD8 + T cells towards Tc1 cells, but 48h-DC most potently, in the presence of exogenous IL-4, favored the induction of Tc2 cells. In vivo, full maturation of DC promoted expansion of Tc2 and fall of Tc1 cells. Tc2 cells maintained a high cytolytic activity and produced significant amounts of IL-4, IL-5, IL-10 and TGF-b. Our results indicate that polarization of naive CD8 + T cells to Tc2 cells is dependent on the amount of time DC have been exposed to maturation stimuli, and might be favored in late and/or chronic phases of an immune response.Supporting information for this article is available at http://www.wiley-vch.de/contents/jc_2040/2006/35597_s.pdf IntroductionUpon antigenic stimulation, T lymphocytes proliferate and acquire a variety of effector functions. Indeed, activation of naive CD4 + T cells in the presence of IL-12 results in the development of Th1 cells, which mainly secrete interferon (IFN)-c, interleukin (IL)-2, tumor necrosis factor (TNF)-a and lymphotoxin, and are commonly associated with a cell-mediated immune response. Conversely, the presence of IL-4 skews the Th response towards Th2 cells producing IL-4, IL-10 and IL-13, relevant cytokines against helminthiasis and allergic diseases [1]. More recently, a third subset of CD4 + T cells has been identified, which express CD25, produce IL-10 and TGF-b, and display regulatory functions [2].The polarization of CD8 + CTL has been less characterized [3]. IL-12 also appears to be critical for the generation of Tc1 cells, characterized by a high production level of IFN-c and cytolytic activity, CC chemokine receptor (CCR)5 expression and the ability to migrate to the inflamed tissues where they are [16], and in many cases their presence was associated with disease severity and progression [13][14][15][16]. In mouse tumor models, IL-4-transduced tumor cells elicited potent antitumor activities [17] and induced Tc2 cells able to cure lung metastases [5,17]. IL-4 produced by CTL was required for the generation of protective tumor-associated CD8 + T cells [5,18]. In other models, Tc2 cells were far less effective in curing subcutaneous tumors [19,20] and lung metastases [21]. Finally, CD8 + T cell subpopulations exhibiting regulatory function have also been described [14,22].Dendritic cells (DC), professional antigen presenting cells (APC) with a unique ability in priming T cell responses [23], play a key role in T cell polarization. In particular, it has been reported that subsets of DC, derived from distinct precursors, induce differenti...

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Dendritic Cells and Cancer: Prospects for Cancer Vaccination

Hart

Jackson²,

Nestle³

2002

Cancer Immune Therapy

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Effective therapeutic cancer vaccination is an old dream, now rekindled by modern advances in cell biology and immunology. Several key facts have inspired the current optimism for clinical immunotherapy trials. First, the realization that, by definition, every malignant cell must express at least one gene product in an abnormal fashion means that theoretically there is at least one tumor-associated antigen (TAA) (it may be an autoantigen) available as a target. Secondly, we now know that any cellular protein (membrane, cytoplasmic or nuclear) may be presented as a peptide, in the context of major histocompatibility complex (MHC) molecules, for recognition by the T lymphocyte receptor complex. Thirdly, whilst it is clear that the immune response has failed the cancer patient, it is also true that it has not suffered irreversible meltdown, i. e. deletion of tumor-reactive T lymphocytes. Finally, it is now recognized that dendritic cells (DCs) are the key cellular elements for initiating and directing immune responses. As DC biology appears to be abnormal in cancer patients, the simplest hypothesis of the day is to use activated DCs to present relevant TAAs to the patient's immune system and thus generate an effective therapeutic response. This chapter will review the physiology of DC biology in the cancer patient, DC preparations and clinical trial results, whilst predicting areas requiring attention in order to optimize DC cancer vaccination for future patient benefit. DC PropertiesDCs originate from CD34 + hematopoietic stem cells, circulate in peripheral blood and are found in virtually all tissues of the body. In peripheral blood, DCs are a morphologically heterogeneous cell population, including DCs with membrane processes (ªmyeloid DCº) and DCs with plasmacytoid morphology (ªplasmacytoid monocytesº, ªplasmacytoid T lymphocyteº, ªlymphoid DCsº) [1,2]. In the skin, DCs are present as epidermal Langerhans cells (LCs) with their characteristic Birbeck ISBNs: 3-527-30441-X (Hardback);(Electronic) 3-527-60079-5 granules [3] and dermal DCs [4,5], which have a subtly different morphology and phenotype. In secondary lymphoid tissues they are present as interdigitating DCs with prominent membrane processes in the T cell area and as ªplasmacytoid monocytesº around high endothelial venules (HEVs) [6]. Monocytes may also differentiate directly into DC-like cells in sites of inflammation [7]. Whilst there is some uncertainty about the identity of the different DC populations and their differentiation, it is clear that a variety of growth factors and cytokines drive DC development [8]. Furthermore, chemokines direct their migration [9] and other soluble compounds influence their function.Blood DCs are commonly defined as lineage negative (Lin ± ), MHC class II positive (MHC-II + ) cells, lacking the CD14 (monocyte), CD3 (T cell), CD19 (B cell) and CD56 [natural killer (NK) cell] lineage markers, but expressing MHC class II molecules at high density, on their surface. They express various adhesion molecules including CD11 a ...

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Relevance of the Tumor Antigen in the Validation of Three Vaccination Strategies for Melanoma

Cited by 119 publications

References 31 publications

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

‘Survival gene’ Bcl-xl potentiates DNA-raised antitumor immunity

Prolonged exposure of dendritic cells to maturation stimuli favors the induction of type‐2 cytotoxic T lymphocytes

Dendritic Cells and Cancer: Prospects for Cancer Vaccination

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