International Immunology Advance Access originally published online on May 4, 2006
International Immunology 2006 18(6):879-886; doi:10.1093/intimm/dxl024
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Melanoma-derived gangliosides impair migratory and antigen-presenting function of human epidermal Langerhans cells and induce their apoptosis
1 EA 37-32, Clinique Dermatologique, Pavillon R, Hôpital E. Herriot, Université Claude Bernard Lyon 1, 69437 Lyon Cedex 03, France
2 Institute of Macromolecular Chemistry, Petru Poni, Iasi, Romania
Correspondence to: J. Péguet-Navarro; E-mail: peguet{at}lyon.inserm.fr
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Gangliosides are ubiquitous, membrane-associated, glycosphingolipids, the composition and production of which is altered in many tumour cells. They have been shown to inhibit the in vitro generation and differentiation of dendritic cells (DCs) from progenitors, but their effect on human tissue-residing DCs is yet to be investigated. In the present study, we analysed the effect of GM3 and GD3 gangliosides purified from human melanoma tumours on the phenotypic and functional maturation of human epidermal Langerhans cells (LCs), the first immune barrier against the tumour cells. We showed that both gangliosides impaired spontaneous LC maturation induced by a short in vitro culture, as assessed by significant down-regulation of co-stimulation (CD40, CD54, CD80, CD86) and maturation markers (CD83, CCR7), which correlated to an impaired ability of the cells to mount allogeneic T cell proliferation. Furthermore, the ganglioside-treated cells displayed less ability to migrate towards CCL19/macrophage inflammatory protein 3 beta, the chemokine that specifically binds CCR7 and mediates LC migration to lymph nodes. Lastly, we showed that both GM3 and GD3 gangliosides enhance LC spontaneous apoptosis. Globally, these in vitro results might explain, at least in part, the altered number and distribution of LCs in melanoma-bearing patients. They underscore a new mechanism for gangliosides to impede the host immune response by inducing LC dysfunction in the tumour microenvironment.
Keywords: dendritic cell, immune suppression, tumour escape, tumour microenvironment
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Dendritic cells (DCs) are heterogeneous professional antigen-presenting cells of bone marrow origin that are critical for the initiation of primary T cell responses (1). There is evidence that DCs play a key role in the induction of tumour-specific immune responses, especially via cross-priming that allows the transfer of antigens from tumour cells to DCs, their presentation through MHC-class I antigens and the generation of CD8+ cytolytic T cells (2, 3). DCs exhibit a broad heterogeneity according to their anatomical location and, due to their accessibility, DCs from epidermis, i.e. Langerhans cells (LCs), are best characterized. LCs comprised 2–4% of epidermal cells and exhibit some characteristic features such as expression of CD1a and the presence of intra-cytoplasmic Birbeck granules, recently identified by langerin (4). LCs play a key role in the initiation of skin immune responses by picking up antigens within the epidermal layer, migrating to regional lymph nodes and stimulating specific T cells. Upon migration, LCs undergo a maturation process characterized by phenotypic changes that render them more efficient in stimulating T cell proliferation. Such changes occur spontaneously when freshly isolated LCs are incubated for some days in culture medium (5). There has been evidence that epidermal LCs can present tumour-associated antigens (6) and may therefore play a key role in the generation of immunity against skin cancers. Most knowledge about the biology of DCs, however, has emerged from the recent possibility to generate DCs in vitro from either cord blood CD34+ progenitors (7) or monocytes (8).
Whereas many studies indicate that most tumours, including melanoma, are immunogenic, they rarely succeed in mounting an efficient immune response. Many mechanisms have been involved in the tumour escape from host immune surveillance. One of them is tumour production of soluble factors that impair DC function, such as vascular-endothelial growth factor (VEGF), macrophage colony-stimulating factor, IL-6 and gangliosides (9, 10).
Gangliosides are ubiquitous, membrane-associated glycosphingolipids, consisting of a ceramide backbone connected to carbohydrates and sialic acids. It has long been known that tumour cells exhibit altered ganglioside composition. For example, whereas normal melanocytes only express GM3, melanoma cells over-express a variety of gangliosides, the majority being GM3 and GD3. Most importantly, unlike normal cells, a number of tumour cells, including melanoma, shed gangliosides into the microenvironment. Many results, from in vitro and animal studies, have shown that gangliosides contribute to the tumour-induced immune suppression (11–13). Shurin et al. (14) first demonstrated that GD2 and GM3 gangliosides from neuroblastoma cell lines inhibit the generation of DCs from CD34+ haematopoietic progenitors. More recently, we showed that gangliosides from human melanoma tumours impair DC differentiation from monocytes and induce their apoptosis (15).
There is evidence that in all epithelial tumours and especially melanoma, the number and distribution of LCs are altered (16, 17). Thus, in the epidermis overlying primary melanoma, LCs decline in number as melanoma progresses, suggesting that as yet unknown melanoma-derived factors might affect the epidermal DCs. In the present study, we analysed, for the first time, the effects of GM3 and GD3 gangliosides purified from human melanoma tumours on the phenotypic and functional maturation of human LCs.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Gangliosides
Gangliosides were purified from human melanoma tumours as previously described (18). GM3 and GD3 were isolated by HPLC on a 250-4 Si100 column (Merck, Darmstadt, Germany) with a Hitachi L-6200 apparatus (Hialeah, FL, USA) using a ternary gradient of hexane–isopropanol–water (55/36/9 to 55/30/15, v/v/v) at a flow rate of 0.25 ml min–1. Fractions of 0.5 ml were collected, and elution was monitored by thin layer chromatography on HPTLC silica gel 60 plates (Merck) migrated in chloroform–methanol–0.2% aqueous calcium chloride (60/35/8, v/v/v). The plates were visualized by heating at 150°C after spraying with a resorcinol–HCl reagent. The ganglioside fractions were pooled, dried and titrated with the periodate–resorcinol method (19). The dried gangliosides were taken up in PBS, pH 7.4, and autoclaved for 20 min at 120°C. The sterile solutions of gangliosides were kept at 4°C until utilization. Fifty-microgram aliquots of each ganglioside were applied on an HPTLC plate along with standards of phosphatidylethanolamine and phosphatidylserine. After migration in chloroform–methanol–water 65/25/4 (by volume), the plate was sprayed with a ninhydrin reagent (0.01% ninhydrin in acetone/water/acetic acid 90/10/1, by volume) and heated 2 min at 120°C in an oven to visualize as red spots all amine-containing compounds.
Culture medium and cytokines
The culture medium was X-VIVO 15 supplemented with 1% gentamicin (Sigma-Aldrich, St Louis, MO, USA). Recombinant human granulocyte macrophage colony-stimulating factor (GM-CSF) (specific activity 2 x 106 U mg–1) was provided by Schering-Plough Research Institute (Kenilworth, NJ, USA) and used at a concentration of 200 U ml–1.
Skin samples and purification of epidermal LCs
Skin samples were obtained from healthy patients undergoing plastic surgery. Skin was freed of fatty tissue and split cut with a keratome set. Skin slices were then incubated with 0.05% trypsin in HBSS without Ca2+ and Mg2+ (Difco Laboratories, Detroit, MI, USA) for 1 h at 37°C. Afterwards, the epidermis was detached from the dermis and placed in HBSS (Gibco, Cergy-Pontoise, France) supplemented with 10% FCS (Invitrogen Corporation) in order to stop the trypsin activity. Epidermal fragments were then minced with fine scissors and single-cell suspension was obtained by repeated pipetting of the epidermal sheets and filtration through sterile gauze. Viability of the cells was 80–90%, as assessed by the trypan blue exclusion test.
Epidermal cell suspension was then layered on Lymphoprep (Axis-Shield PoC AS, Oslo, Norway) and centrifuged for 20 min at 400 g. The cells recovered from the interface were washed and enumerated. Routinely, they contained 15–30% LCs, as assessed by phase contrast analysis. In contrast to keratinocytes, LCs exhibit short cell processes. For the second enrichment step, LC-enriched suspension was layered on Lymphoprep previously diluted with distilled water (14 ml/36 ml Lymphoprep) and centrifuged at 400 g for 20 min. LCs were recovered from the interface, washed extensively and counted. As assessed by immunofluorescence staining with anti-HLA-DR mAb (B8.12.2; Immunotech, Marseille, France), the resulting population routinely contained 70–90% LCs.
LC treatment with gangliosides
LCs (106 cells ml–1) were incubated for 1 or 2 days in the presence or absence of GM3 or GD3 gangliosides at different concentrations, in X-VIVO medium supplemented with GM-CSF and antibiotics. In additional experiments, after addition to the X-VIVO medium of GD3 ganglioside (100 µg), medium depletion in GD3 was achieved by incubation for 30 min at 4°C with either murine anti-GD3 mAb (250 µg; clone 4F6, produced in our laboratory) or irrelevant mouse Ig (250 µg; Immunotech) as control, in the presence of pan mouse Ig-coated magnetic Dynabeads (Dynal-Biotech SA, Oslo, Norway). The preparation was then applied to a magnet; the bead-free medium was recovered and used in the assays.
Immunofluorescence staining and flow cytometry analysis
LCs were stained with a panel of mAbs, either after isolation or after a 2-day culture in the presence or absence of gangliosides. Incubation with the different mAbs was carried out for 30 min at 4°C and controls were carried out with irrelevant isotype-matched Igs. Cells were washed and, for indirect staining, further incubated for 30 min at 4°C with FITC- or PE-conjugated F(ab)2 fragments of goat anti-mouse antibody. The following mAbs were used: anti-CD1a–FITC (NA1/34) from DAKO (Glostrup, Denmark); anti-HLA-DR–FITC (B8.12.2), anti-CD54–FITC (84H10), anti-CD80–FITC (MAB 104), anti-CD83–FITC (HB15a), anti-langerin–PE (DCGM4), anti-DC-LAMP–PE (104.G4), all from Immunotech; anti-CD40–FITC (EA-5) from Biosource International (Camarillo, CA, USA); anti-CD86–FITC (2331-FUN-1) from BD Pharmingen (San Diego, CA, USA) and anti-CCR7–FITC (150 503) and anti-CCR6–FITC (53 103.111) from R&D Systems (Mineapoplis, MN, USA). Fluorescence analysis was performed on 104 cells using a flow cytometer (Becton Dickinson, Mountain View, CA, USA) and the Cell Quest software.
Mixed lymphocyte reaction
The ability of the LCs to induce proliferation of allogeneic T cells served as a functional assay. Allogeneic T cells were isolated from the peripheral blood of allogeneic donors, by rosetting with sheep red blood cells as previously described (20). The T cell population contained 95% CD3, as assessed by flow cytometry. Mixed lymphocyte reactions (MLRs) were carried out in round-bottom microtiter plates by adding 105 allogeneic T cells to varying numbers of DCs. Triplicate cultures were maintained for 5 days at 37°C in a 5% CO2 humidified atmosphere. T cell proliferation was measured by pulsing the cells with 1 µCi of [3H]methylthymidine (25 Ci/mmol; Amersham Pharmacia Biotech, Les Ulis, France) for the final 18 h of culture. Cells were then harvested, and incorporated thymidine was quantitated in a direct beta counter (Matrix 96; Packard Instruments, Meriden, CT, USA). Results were expressed as the mean counts per minute ± SD of triplicate cultures.
Apoptosis
The early exposure of phosphatidylserine residues on the cell surface was measured using the annexin-V–FITC kit, with dead cells identified by propidium iodide (Immunotech). For this assay, 5000 events were collected on a FACScan II cytometer and analysed with Cell Quest software.
Migration assay
LC migration in response to the CCL19/macrophage inflammatory protein 3 beta (MIP3ß) chemokine was assessed using 24-transwell plates with 8.0-µm pore size membrane (Becton Dickinson France S.A). After 1-day culture, in the presence or absence of gangliosides, LCs (2 x 105 viable cells) were seeded into the upper chamber of the transwell system and CCL19/MIP3ß (25 µg ml–1, R&D Systems) was added in the lower chamber. After an incubation period of 6 h at 37°C, the viable cells that had migrated from the underside of filter were enumerated. LCs can be easily identified through their dendritic processes. Control experiments were carried out in the absence of the chemokine to assess spontaneous migration. Some assays have been carried out using the GD3-depleted ganglioside fraction.
Statistical analysis
Statistical analysis was carried out using the Student's t-test. Values of P < 0.05 were considered as statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Purity of ganglioside fractions
Thin layer chromatography was carried out to assess the purity of the melanoma-derived ganglioside fractions. As shown in Fig. 1(A), the GM3 and GD3 fractions were free of other lipids and not contaminated by any peptidic material (Fig. 1B).
|
Melanoma-derived GM3 and GD3 gangliosides impair spontaneous LC maturation
As shown in Fig. 2(A), freshly isolated LCs displayed an immature phenotype, characterized by high expression of CD1a and langerin, the specific LC marker. The cells expressed CCR6, the receptor for CCL20/MIP3
chemokine, and displayed significant HLA-DR staining but did not express or only slightly expressed the co-stimulation (CD40, CD54, CD80, CD86) and maturation (CD83, DC-LAMP, CCR7) markers. By contrast, after a 2-day incubation in serum-free medium, LCs matured, as evidenced by up-regulation of HLA-DR and all the above-mentioned co-stimulation and maturation molecules. At the same time, the cells down-regulated CD1a and langerin staining, lost CCR6 expression and acquired that of CCR7, the receptor for CCL20/MIP3ß chemokine, which mediates LC migration to regional lymph nodes. LC exposure to both GM3 and GD3 gangliosides profoundly impaired the cell maturation, as shown in Fig. 2(A), which illustrates a representative experiment, and Table 1, which summarizes the results from five independent experiments carried out with different donors. Especially, ganglioside-treated LCs retained high langerin expression, whereas up-regulation of CD40, CD54, CD80, CD86, CD83 and CCR7 was statistically decreased, as assessed by the Student's t-test. DC-LAMP and HLA-DR staining also tended to decrease, although the data were not statistically significant. The effect of gangliosides was dose dependent, observed with at least 30 µg ml–1 GM3 and 50 µg ml–1 GD3 (not shown), GM3 being, therefore, more efficient than GD3 in this process.
|
|
In order to assess the specificity of the ganglioside effects, anti-GD3 mAb and Ig-coated magnetic beads were used to deplete the ganglioside, prior to LC incubation. As assessed by thin layer chromatography, the technique allows almost complete removal of GD3 from the preparation (Fig. 3). More interestingly, GD3 depletion also reversed the phenotypic alterations, therefore, demonstrating the specificity of the effect (Fig. 2B).
|
GM3 and GD3 gangliosides inhibit LC migration towards the CCL19/MIP3ß chemokine
We analysed whether the ganglioside-induced down-regulation of CCR7 expression on human LCs had functional relevance, regarding migration of the cells towards CCL19/MIP3ß, the chemokine that specifically binds CCR7. To this end, LCs were pre-treated with gangliosides (GM3 40 µg ml–1, GD3 100 µg ml–1) or medium alone and a similar number of viable cells were introduced into the upper compartment of transwells. Cells were allowed to migrate for 6 h into the lower compartment containing culture medium supplemented with or without MIP3ß.
As shown in Fig. 4(A), the LC migratory capacity towards MIP3ß was significantly reduced after treatment with either GM3 or GD3. By contrast, the ganglioside pre-treatment did not substantially affect the number of the few viable cells spontaneously migrating in the absence of the chemokine (not shown), which argues against a mere cytotoxic effect.
|
Furthermore, the GD3-depleted preparation failed to inhibit LC migration in the presence of MIP3ß, therefore, attesting the specificity of the effect (Fig. 4B).
GM3- or GD3-treated LCs are poor stimulators of primary allogeneic T cell responses
DC expression of co-stimulatory molecules plays a key role in T cell activation. We thus wondered whether altered LC phenotypic maturation in the presence of gangliosides correlated with impaired allostimulatory function. To this end, LCs were recovered after the 2-day culture in the presence or absence of GM3 or GD3. Graded numbers of viable LCs were then added to allogeneic T cells in a MLR assay. As shown in Fig. 5, LC allostimulatory function was significantly reduced after LC incubation with either GM3 or GD3 gangliosides.
|
70 counts per minute.GM3 and GD3 gangliosides from melanoma tumours enhance LC apoptosis
In all the experiments, we observed that LC treatment with gangliosides decreased cell viability at the end of the culture (data not shown). We asked, therefore, whether this effect might be due to an induction of apoptosis. Since LCs spontaneously became apoptotic and rapidly died upon in vitro culture (21), experiments were carried out after a shorter incubation with gangliosides (18 h). As assessed by double staining with annexin-V and propidium iodide, both GM3 and GD3 increased the number of apoptotic LCs (Fig. 6A).
|
We next wondered whether the inhibitory effect of gangliosides on LC maturation merely correlates with the induction of cell apoptosis. As shown in Fig. 6(B), however, both annexin-negative and -positive LCs displayed decreased expression of HLA-DR and CD83, suggesting, therefore, that the ganglioside-induced LC apoptosis and impaired maturation were two independent events.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
There has been now much evidence that gangliosides shed from tumours affect in vitro DC differentiation from precursors. Thus, addition of neuroblastoma-derived GD2 and GM3 gangliosides to murine or human haematopoietic progenitors inhibited the generation of functionally active DCs (14) and both bovine brain ganglioside mixture and melanoma-derived gangliosides impaired DC differentiation from human monocytes (15, 22). The present study extends these results by showing, for the first time, that melanoma-derived GM3 and GD3 gangliosides impair the in vitro phenotypic and functional maturation of human resident epidermal LCs, the first immune barrier against melanoma cells. Gangliosides GM3 and GD3 were purified from a pool of human melanoma tumours, but not from melanoma cell lines. Indeed, melanoma cell lines in culture are known to modify their constitutive gangliosides by expressing new structures containing N-glycolylneuraminic acid taken up from the FCS used in culture medium (23). Moreover, these new structures are highly antigenic in humans. Accordingly, care should be taken to avoid as much as possible using gangliosides purified from melanoma cell lines, especially for studies dealing with the human immune system.
LC phenotypic and functional alterations occurred with ganglioside concentrations close to those found in the peripheral blood of melanoma patients. One can hypothesize that higher concentrations of gangliosides can be found in the vicinity of tumours. Indeed, we have previously shown that the lymphocytes of tumour-bearing patients are enriched in gangliosides derived from the tumours (18). This suggests, therefore, that our in vitro findings may be in vivo relevant.
One could assume that spontaneous immune response against melanoma might be elicited by neighbouring DCs, which mature in response to tumour-derived inflammatory signals and migrate to the regional lymph nodes. However, there is evidence that, as yet unknown, tumour-derived factors might impair DC migration. Thus, monocyte-derived DCs conditioned by melanoma supernatant did not migrate in response to CCL21 (24) and in vitro generated DCs injected in melanoma tumours failed to home into draining lymph nodes (25). In the mouse, the presence of a tumour was associated with a defective LC migration to lymph nodes, following hapten skin sensitization (26). Moreover, a marked decrease in interdigitating DCs was observed in the lymph nodes closed to a primary melanoma (27). We showed here that GM3- and GD3-treated LCs displayed down-regulated CCR7 expression and, concurrently, impaired migratory property towards CCL19/MIP3ß. The results strongly suggest that melanoma-derived gangliosides may play a role in the altered LC migration to lymph nodes and, accordingly, the elicitation of primary immune response.
Acquisition of co-stimulation and maturation molecules at the cell surface is thought to be a pre-requisite for DCs to induce efficient anti-tumour immunity (28). We found here that both GM3 and GD3 gangliosides down-regulated the expression of co-stimulation and maturation markers on 2-day cultured LCs, making them less efficient in mounting primary allogeneic T cell responses. Inasmuch as in vitro LC incubation is thought to mimic the in vivo LC migration to lymph nodes (5), one could expect that LC trafficking from melanoma-bearing skin would be poor inducers of efficient immune responses. In line with this, a recent study pointed to the pivotal role of mature DCs in the sentinel lymph node of melanoma patients, in the elicitation of anti-tumour immune response (29). Moreover, reports from many laboratories have unravelled that the DC activation/maturation state governs the nature of the T cell response, i.e. its polarization towards Th1, Th2 or regulatory T cells. Although the question has not been addressed here, it would be interesting to analyse whether stimulation with ganglioside-treated LCs could bias the T cell response and induce tolerance, as was observed in most melanoma patients. In line with this, a recent paper (30) reported that exposure of monocyte-derived DCs to GD1a ganglioside inhibited the development of both Th1 and Th2 responses, which could hinder the generation of effective anti-tumour immune response.
As previously described (21), purified LCs undergo spontaneous apoptosis, which made them rather bad models for studying this process. However, by shortening the LC culture, we showed that gangliosides enhance LC apoptosis, which confirms our previous results using monocyte-derived DCs. The data are in line with immunohistochemical studies that reveal the presence of apoptotic DCs within human melanoma tumours (31) and suggest that gangliosides might be, at least in part, responsible for this process.
In a previous paper (32), using a 2-day co-culture in transwells, we showed that melanoma cell clones inhibited the differentiation of human CD34+ cord blood progenitors into DCs, but had no effect on the in vitro maturation of human epidermal LCs. One of the clones, however, was expected to release both GM3 and GD3 gangliosides. The discrepancy between these and the present results is unclear but most likely related to an insufficient amount of gangliosides released by the growing melanoma monolayer cells during the short-term experiment. It suggests, however, that progenitors are more sensitive than differentiated LCs to the tumour-induced inhibitory effects.
Many other melanoma-derived soluble factors have been shown to impair in vitro generated DCs, but very few studies have been carried out using LCs. VEGF was shown to be involved in the defective LC function in tumour-bearing mice, but most probably via an inhibition of epidermis recolonization from precursors (26). In line with this, we failed to demonstrate any effect of VEGF A (5–50 ng ml–1) on the in vitro phenotypic and functional LC maturation (data not shown). By contrast, we showed that IL-10, that is over-expressed in melanoma, strongly impaired human LC function (33) and might, therefore, participate in the tumour-induced local immunosuppression.
Finally, if our in vitro data could be extrapolated to what occurs in vivo, they might explain many LC features encountered in melanoma patients such as epidermal depletion, impaired homing to lymph nodes and, finally, incapacity to mount efficient immune response. It is therefore tempting to speculate that the effects of melanoma-derived gangliosides on human LCs might be an additional mechanism for melanoma to escape from immune surveillance. The results underscore the potential role for gangliosides in altering the tumour microenvironment and the host immune response. Accordingly, they support the concept that depletion of the shed glycosphingolipids might improve DC function in melanoma-bearing patients and might serve to improve the efficacy of cancer immunotherapy.
|
Abbreviations |
|---|
| DC, dendritic cell |
| LC, Langerhans cell |
| MIP3ß, macrophage inflammatory protein 3 beta |
| MLR, mixed lymphocyte reaction |
|
Notes |
|---|
Transmitting editor: J. Borst
Received 9 May 2005, accepted 12 March 2006.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
- Steinman RM. (1991) The dendritic cell system and its role in immunogenicity. Annu. Rev. Immunol 9:271.[CrossRef][ISI][Medline]
- Huang AY, Golumbek CP, Ahmadzadeh M, Jaffee E, Pardoll D, Levisky H. (1994) Role of bone-marrow derived cells in presenting MHC-class I-restricted tumor antigens. Science 264:961.
[Abstract/Free Full Text] - Armstrong TD, Pulaski BA, Ostrand-Rosenberg S. (1998) Tumor antigen presentation: changing the rules. Cancer Immunol. Immunother 46:70.[CrossRef][ISI][Medline]
- Valladeau J, Ravel O, Dezutter-Dambuyant C, et al. (2000) Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules. Immunity 12:71.[CrossRef][ISI][Medline]
- Romani N, Lenz A, Glassel H, et al. (1989) Cultured human Langerhans cells resemble lymphoid dendritic cells in phenotype and function. J. Invest. Dermatol 93:600.[CrossRef][ISI][Medline]
- Grabbe S, Bruvers S, Gallo RL, Knisely TL, Nazareno R, Grandstein RD. (1991) Tumor antigen presentation by murine epidermal cells. J. Immunol 146:3656.[Abstract]
- Caux C, Dezutter-Dambuyant C, Schmitt D, Banchereau J. (1992) GM-CSF and TNF a cooperate in the generation of dendritic Langerhans cells. Nature 360:258.[CrossRef][Medline]
- Sallusto F and Lanzavecchia A. (1994) Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony-stimulating factor plus interleukin 4 and down-regulated by tumor necrosis factor A. J. Exp. Med 179:1109.
[Abstract/Free Full Text] - Shurin MR and Gabrilovich DI. (2001) Regulation of dendritic cell system by tumor. Cancer Res. Ther. Control 11:65.
- Gabrilovich D. (2004) Mechanisms and functional significance of tumour-induced dendritic cell defects. Nature Rev. Immunol 4:941.[CrossRef][ISI][Medline]
- Ladisch S, Li R, Olson E. (1984) Ceramide structure predicts ganglioside immunosuppressive activity. Proc. Natl Acad. Sci. USA 91:1974.
- Heitger A and Ladisch S. (1996) Gangliosides block antigen presentation by human monocytes. Biochem. Biophys. Acta 1303:161.[Medline]
- McKallip R, Li R, Ladisch S. (1999) Tumor gangliosides inhibit the tumor-specific immune response. J. Immunol 163:3718.
[Abstract/Free Full Text] - Shurin GV, Shurin MR, Bykovskaia S, Shogan J, Lotze MT, Barksdale EM. (2001) Neuroblastoma-derived gangliosides inhibit dendritic cell generation and function. Cancer Res 61:363.
[Abstract/Free Full Text] - Péguet-Navarro J, Sportouch M, Popa I, Berthier O, Schmitt D, Portoukalian J. (2003) Gangliosides from human melanoma tumours impair dendritic cell differentiation from monocytes and induce their apoptosis. J. Immunol 170:3488.
[Abstract/Free Full Text] - Stene MA, Babajanians M, Bhuta S, Cochran AJ. (1988) Quantitative alterations in cutaneous Langerhans cells during the evolution of malignant melanoma of the skin. J. Invest. Dermatol 91:125.[CrossRef][ISI][Medline]
- Toriyama K, Wen DR, Paul E, Cochran AJ. (1993) Variations in the distribution, frequency and phenotype of Langerhans cells during the evolution of malignant melanoma of the skin. J. Invest. Dermatol 100:269s.[CrossRef][Medline]
- Portoukalian J, Zwingelstein G, Abdul-Malak N, Doré JF. (1978) Alteration of gangliosides in plasma and red cells of humans bearing melanoma tumors. Biochem. Biophys. Res. Commun 85:916.[ISI][Medline]
- Jourdian GW, Dean L, Roserman S. (1971) The sialic acids. XI. A periodate-esorcinol method for the quantitative estimation of free sialic acids and their glycisides. J. Biol. Chem 430:435.
- Kaplan ME and Clark C. (1974) An improved rosetting assay for detection of human T lymphocytes. J. Immunol. Methods 5:131.[CrossRef][ISI][Medline]
- Ludewig B, Graf D, Gelderblom HR, Becker Y, Kroczek RA, Pauli G. (1995) Spontaneous apoptosis of dendritic cells is efficiently inhibited by TRAP (CD40-ligand) and TNF, but strongly enhanced by interleukin-10. Eur. J. Immunol 25:1943.[ISI][Medline]
- Wölfl M, Batten WY, Posivsky C, Bernhard H, Berthold F. (2002) Gangliosides inhibit the development from monocytes to dendritic cells. Clin. Exp. Immunol 130:441.[CrossRef][ISI][Medline]
- Furukawa K, Thampoe IJ, Yamaguchi H, Lloyd KO. (1989) The addition of exogeneous gangliosides to cultured human cells results in a cell-specific expression of novel surface antigens by a biosynthetic process. J. Immunol 142:848.[Abstract]
- Remmel E, Terracciano L, Noppen C, et al. (2001) Modulation of dendritic cell phenotype and mobility by tumor cells in vitro. Hum. Immunol 62:39.[CrossRef][ISI][Medline]
- Triozzi PL, Khurram R, Aldrich WA, Walker MJ, Kim JA, Jaynes S. (2000) Intratumoral injection of dendritic cells derived in vitro in patients with metastasic cancer. Cancer 89:2646.[CrossRef][ISI][Medline]
- Ishida T, Oyama T, Carbone DP, Gabrilovich DI. (1998) Defective function of Langerhans cells in tumor-bearing animals is the result of defective maturation from hemopoietic progenitors. J. Immunol 161:4842.
[Abstract/Free Full Text] - Lana AM, Wen DR, Cochran AJ. (2001) The morphology, imunophenotype and distribution of paracortical dendritic leukocytes in lymph nodes regional to cutaneous melanoma. Melanoma Res 11:401.[CrossRef][ISI][Medline]
- Allison JP, Hurwitz AA, Leach DR. Manipulation of costimulatory signals to enhance anti-tumor T cell responses. Curr. Opin. Immunol 7:682.
- Movassagh M, Spatz A, Davoust J, et al. (2004) Selective accumulation of mature DC-Lamp+ dendritic cells in tumor sites is associated with efficient T-cell-mediated antitumor response and control of metastasic dissemination in melanoma. Cancer Res 64:2192.
[Abstract/Free Full Text] - Shen W, Falahati R, Stark R, Leitenberg D, Ladisch S. (2005) Modulation of CD4 Th cell differentiation by ganglioside GD1a in vitro. J. Immunol 175:4927.
[Abstract/Free Full Text] - Esche C, Lokshin A, Shurin GV, et al. (1999) Tumor's other immune targets: dendritic cells. J. Leukoc. Biol 66:336.[Abstract]
- Berthier-Vergnes O, Gaucherand M, Péguet-Navarro J, et al. (2001) Human melanoma cells inhibit the earliest differentiation steps of human Langerhans cell precursors but failed to affect the functional maturation of epidermal Langerhans cells. Br. J. Cancer 85:1944.[CrossRef][ISI][Medline]
- Péguet-Navarro J, Moulon C, Caux C, Dalbiez-Gauthier C, Banchereau J, Schmitt D. (1994) Interleukin-10 inhibits the primary allogeneic T cell response to human epidermal Langerhans cells. Eur. J. Immunol 24:884.[ISI][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J. de Leon, A. Fernandez, M. Clavell, M. Labrada, Y. Bebelagua, C. Mesa, and L. E. Fernandez Differential influence of the tumour-specific non-human sialic acid containing GM3 ganglioside on CD4+CD25- effector and naturally occurring CD4+CD25+ regulatory T cells function Int. Immunol., April 1, 2008; 20(4): 591 - 600. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||