Immune escape mechanisms in malignant melanoma.

Geertsen, Ralf; Hofbauer, Günther F.L.; Kamarashev, Jivko; Yue, Feng-Yun; Dummer, Reinhard

doi:10.3892/ijmm.3.1.49

Cited by 19 publications

(17 citation statements)

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“…49 -52,69 This raises the question why no increased IgG and IgM titers can be found in patients with advanced melanoma before ganglioside vaccination. While several immune escape mechanisms including MHC loss or TAP deficiency have been reported (reviewed in 70 ), IL-10-mediated down-regulation of CD1 molecules on the surface of tumor-infiltrating APC may offer an explanation for the lacking humoral immune response against tumor-associated glycolipid antigens observed in unvaccinated metastatic melanoma patients.…”

Section: Discussionmentioning

confidence: 99%

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Gerlini

Tun-Kyi

Dudli

et al. 2004

The American Journal of Pathology

127

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CD1 molecules are expressed by antigen-presenting cells such as dendritic cells and mediate primary immune responses to lipids and glycolipids which have been shown to be expressed by various tumors. Glycolipids are expressed by melanoma cells but, despite their immunogenicity, no efficient spontaneous immune responses are elicited. As IL-10 has previously been shown to down-regulate CD1a on dendritic cells and is known to be expressed by various melanoma cell lines, we investigated if melanoma-derived IL-10 could down-regulate CD1 molecule expression on dendritic cells as a possible way to circumvent immune recognition. We found that CD1a, CD1b, CD1c, and CD1d were significantly down-regulated on dendritic cells in metastatic (n ‫؍‬ 10) but not in primary melanoma lesions (n ‫؍‬ 10). We further detected significantly higher IL-10 protein levels in metastatic than in primary melanomas. Moreover, supernatants from metastatic melanomas were significantly more effective in down-regulating CD1 molecules on dendritic cells than supernatants from primary melanoma cultures. This effect was blocked using a neutralizing IL-10 antibody in a dose dependent manner. Our findings suggest that metastatic but not primary melanomas can down-regulate CD1 molecules on infiltrating dendritic cells by secreting IL-10 which may represent a novel way to escape the immune response directed against the tumor. CD1 molecules are cell surface glycoproteins and represent a non-classical, non-polymorphic antigen-presenting system which is distantly related to major histocompatibility complex (MHC) class I and class II molecules. While MHC molecules form complexes with peptides, the CD1 system presents lipids and glycolipids of self and foreign origin.

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Section: Discussionmentioning

confidence: 99%

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Gerlini

Tun-Kyi

Dudli

et al. 2004

The American Journal of Pathology

127

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“…26,48,[53][54][55][56][57][58][59] In 32 of 56 NPC lesions, we investigated the HLA class I antigen (b-microglobulin) and HLA class II antigen (HLA-DR), and co-stimulatory molecule CD54. These molecules are very important for antigens presenting or for activating T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

Li¹,

Zhang²,

Xie³

et al. 2007

Cancer Biology & Therapy

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To understand the role of Epstein-Barr virus (EBV) and viral products in associated with immunophenotype and clinical outcome of primary nasopharyngeal carcinoma (NPC), the expression levels of chemokines IFN-g-induced protein 10 (IP-10, CXCL10), stromal-derived factor-1 (SDF-1, CXCL12) and its receptor CXCR4 was investigated in 56 primary NPC biopsy specimens from Chinese NPC patients in parallels with LMP1 antigen and EBER1 by immunohistochemisty (IHC) and in situ hybridization (ISH). Moreover, the expression levels of HLA class I (b-microglobulin) and II antigen (HLA-DR), and co-stimulatory molecule CD54 were also evaluated in 31 out of these 56 patients using immunohistochemisty (IHC). Our results showed that (a) the elevated expression levels of IP10, SDF-1, CXCR4, b-microglobulin, HLA-DR and CD54 in NPC lesions was 66%, 36%, 30%, 42%, 55% and 69%, respectively. The differentiated nonkeratinizing and undifferentiated types of nasopharyngeal carcinoma (NPC) are associated with Epstein-Barr virus (EBV) in South China, which has the highest incidence rate in the world. 1 The EBV latent type II antigens include nuclear antigen 1 (EBNA1), and latent membrane protein 1 (LMP1, in approximately 50%, seen in ref.2) and protein 2 (LMP2), in addition small non-polyadenylated viral RNAs non-coding nuclear RNAs (EBERs) and BamHI-A rightward transcripts (BARTs) expressed in NPC tumor cells. The expressions of EBV antigens in NPC tumor cells provide the targets for adoptive immunotherapy. [3][4][5][6] However, the poorly differentiated NPC is always characterized by the presence of a highly cellular lymphoid stroma admixed with tumor cells. 7 However, the role of local immunity surrounding NPC cells and the role EBV and viral products expressed in tumor cell remain unclear, which is associated with the expression of immune-related molecules including chemokines and receptors, HLA class I and II antigens, and co-stimulatory molecules and the role of EBV and viral products to alter the expression of immune-related molecules on tumor cells. It has been reported that the expression pattern of immune related-molecules on tumor cells will affect the outcome of T-cell-based adoptive immunotherapy for NPC. [8][9][10] In the tumor bed, chemokines and cytokines are secreted by both tumor-infiltrating immune cells and the tumor cells, and these chemokines and cytokines are capable of pleiotropic effects. 8 For example, IP-10 is a CXC chemokine produced by endothelial cells and macrophages post-stimulated by IFNg. IP-10 can induce rapid and transient adhesion of human IL-2-stimulated T lymphocytes to endothelial cells through its receptor CXCR3, which is selectively expressed on activated T cells. It is thought that expression of IP-10 in tumor cells induces potent anti-tumor functions, such as induction of the Th1 immune response and inhibition of angiogenesis. 11-13 SDF-1 is a a-chemokine, and bind to the only receptor CXCR4. Recent studies suggested that the SDF-1/CXCR4 axis play an important and unique role not only in th...

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“…The strategy of helper T cell-assisted induction of CTL responses was tested in cell culture assays and mouse models, and the clinical responses and induction of mimotope-specific T cell responses (as measured by intracellular IFN-+ and cytolysis assays) reported here indicate the effectiveness of this strategy in humans as well. Antigen loss has been described as a major cause for failing cancer immune therapies [36][37][38]. In the present study, tumor antigenicity and susceptibility to CTL lysis was maintained, even during the final disease stage.…”

Section: Discussionmentioning

confidence: 50%

Anti‐tumor immune responses and tumor regression induced with mimotopes of a tumor‐associated T cell epitope

et al. 2003

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Mimotopes provide an alternative to natural T cell epitopes for cancer immune therapy, as they can recruit and stimulate T cell repertoires that deviate from the repertoires engaged with the tumor and exposed to disease-related immune suppression. Here, mimotopes of a shared tumor-associated T cell epitope in cutaneous lymphoma were tested for their capacities to induce clinical and immunological responses in cancer patients. The mimotope sequences had been determined by a combinatorial peptide library approach without knowledge of the corresponding natural tumor-associated antigen. Vaccination with these mimotopes together with helper T cell-inducing antigens led to complete tumor remission in the two patients tested. After each booster vaccination, enhanced frequencies of mimotopespecific CD8 + T cells were detected in the peripheral blood of the patients, and the CTL proved to be cytotoxic and tumoricidal when tested in vitro. These data provide a first indication of clinical efficacy of mimotopes in cancer patients.

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Immune escape mechanisms in malignant melanoma.

Cited by 19 publications

References 0 publications

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Metastatic Melanoma Secreted IL-10 Down-Regulates CD1 Molecules on Dendritic Cells in Metastatic Tumor Lesions

Expression of immune-related molecules in primary EBV positive chinese nasopharyngeal carcinoma: Associated with latent membrane protein 1 (LMP1) expression

Anti‐tumor immune responses and tumor regression induced with mimotopes of a tumor‐associated T cell epitope

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