Differential clinical significance of individual NKG2D ligands in melanoma: soluble ULBP2 as an indicator of poor prognosis superior to S100B.

Purpose: Cytotoxic lymphocytes interact with human tumor cells via the activating immunoreceptor NKG2D, recognizing a variety of stress-associated MIC and ULBP surface molecules. However, tumors can escape from this immunosurveillance by shedding NKG2D ligands (NKG2DL), rendering the soluble products detectable in patients' sera.

Experimental Design: To elucidate the clinical significance of NKG2DL diversity, we studied their expression on melanoma tissues and their presence as soluble molecules in sera from >200 melanoma patients and compared the latter with the well-established serum marker S100B.

Identification of heme oxygenase-1-specific regulatory CD8+ T cells in cancer patients.

Treg deficiencies are associated with autoimmunity. Conversely, CD4+ and CD8+ Tregs accumulate in the tumor microenvironment and are associated with prevention of antitumor immunity and anticancer immunotherapy. Recently, CD4+ Tregs have been much studied, but little is known about CD8+ Tregs and the antigens they recognize.

Meeting report: consensus from the first and second Global Workshops in Melanoma November 19-20, 2008.

This overview of the current state of melanoma research and treatment and directions for moving forward represents the consensus of discussions between expert panelists at the First and Second Global Workshops on Melanoma held in Fajardo, Peurto Rico on November 30-December 1, 2007 and Clearwater Beach, Florida on November 19-20, 2008.

Tumor biomarkers in melanoma.

Background: Morphologic and histopathologic markers have been the backbone for the classification and prognostic assessment of melanoma. Availability of an increasing number of molecular markers, however, provides the potential for refining diagnostic and prognostic categories in this disease.

Methods: We reviewed the recent data that are accumulating concerning gene expression and genetic profiling and related these to clinical aspects of the disease.

Oligoclonal CD4+ T cells promote host memory immune responses to Zwitterionic polysaccharide of Streptococcus pneumoniae.

Zwitterionic polysaccharides of the normal flora bacteria represent a novel class of antigens in that they correct systemic CD4(+) T-cell deficiencies and direct lymphoid organogenesis during colonization of the host. Presentation of these polysaccharides to CD4(+) T cells depends on major histocompatibility complex class II- and DM-dependent retrograde transport from lysosomes to the cell surface. Yet the phenotype and clonality of the immune response to the polysaccharide in the mature host immune system have not been studied.

Human Merkel cell polyomavirus infection II. MCV is a common human infection that can be detected by conformational capsid epitope immunoassays.

Merkel cell polyomavirus (MCV) is a newly-discovered human tumor virus found in approximately 80% of Merkel cell carcinoma (MCC). The rate of MCV infection among persons without MCC is unknown. We developed a MCV virus-like particle (VLP) enzyme-linked immunoassay (EIA) that does not cross-react with human BK or murine polyomaviruses.

Molecular pathogenesis of Merkel cell carcinoma.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer which is twice as lethal as melanoma as more than one-third of MCC patients will die from this cancer. Although MCC, which primarily affects elderly and immune suppressed individuals, is very rare to date, its incidence is rapidly increasing. In contrast to the immense progress that has been made in the elucidation of the molecular pathogenesis of other cancer entities, until recently there were no clear-cut indications which events drive the carcinogenesis of MCC.

Identification and characterization of survivin-derived H-2Kb-restricted CTL epitopes.

Survivin is overexpressed in several malignancies and in tumor-associated endothelium making it an attractive target for therapeutic cytotoxic T-cell responses. Thus, it would be important to test this notion in preclinical models. Consequently, we screened the murine survivin sequence for potential binding K(b)-restricted octamer peptide epitopes.

Melanoma inhibitor of apoptosis protein (ML-IAP) specific cytotoxic T lymphocytes cross-react with an epitope from the auto-antigen SS56.

A large proportion of melanoma patients host a spontaneous T-cell response specifically against ML-IAP-derived peptides. In this study, we describe that some ML-IAP-specific cytotoxic T cells isolated from melanoma patients cross react with an epitope from the auto-antigen SS56. SS56 is a recently described target of autoantibody responses in Sjögren's syndrome (SS) as well as systemic lupus erythematosus (SLE).

Therapy of metastasized Merkel cell carcinoma with liposomal doxorubicin in combination with radiotherapy.

Background: Merkel cell carcinoma is a rare skin cancer of neuroendocrine origin, which is characterized by a high rate of recurrence, metastatic spread and mortality. Because of its rarity, evidence-based therapeutic regimens are difficult to establish. Merkel cell carcinoma is known to be both radio- and chemosensitive.

CD147 impacts angiogenesis and metastasis formation.

CD147 is highly expressed on many tumor cells; its role for tumor invasiveness and metastasis has been deduced from its capacity to induce MMPs, i.e., MMP-1, -2, -3, and -9.

Overexpression of the KIT/SCF in uveal melanoma does not translate into clinical efficacy of imatinib mesylate.

Purpose: Recently, gene amplification and overexpression of KIT as well as activating mutations in the KIT gene have been described to occur in certain subsets of melanoma. These findings suggest KIT as a potential target for therapy with imatinib mesylate in these melanomas. To date, data on the KIT status in uveal melanoma (UM) is limited.

Merkel cell carcinoma: molecular pathogenesis, clinical features and therapy.

Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin. The incidence of this rare tumor is increasing rapidly; the American Cancer Society estimates for 2008 almost 1500 new cases in the U.S.

The immunodominant HLA-A2-restricted MART-1 epitope is not presented on the surface of many melanoma cell lines.

Among the relatively large number of known tumor-associated antigens (TAA) which are recognized by human CD8 T-cells, Melan-A/MART-1 is one of the most-if not the most-frequently used target for anti-cancer vaccines in HLA-A2 + melanoma patients. In this study, we analyzed the killing of a large panel of melanoma cells by a high avidity, MART-1-specific T-cell clone or a MART-1-specific, polyclonal T-cell culture. Strikingly, we observed that the MART-1-specific T-cells only killed around half of the analyzed melanoma cell lines.

Proliferation arrest in B-Raf mutant melanoma cell lines upon MAPK pathway activation.

Due to elaborate control mechanisms, in benign tumors the activation of oncogenes primarily induces senescence, associated with cessation of cellular proliferation; for example, melanocytic nevi expressing mutant B-Raf. These mechanisms include the RB and/or the p53 pathway. The current model of melanomagenesis postulates that progression to immortal melanoma cells requires inactivating aberrations in signaling cascades controlling senescence.

BRAFV600E mutations in malignant melanoma are associated with increased expressions of BAALC.

Unlabelled: BACHGROUND: Activating BRAF mutations are present in approximately 50% of melanomas. Although different downstream target genes of the most common mutant V600E have been identified, the contribution of activating BRAF mutations to malignant transformation needs further clarification.

Methods: Microarray gene analysis was performed for human melanoma cell lines harboring BRAFV600E mutations in comparison to cell lines without this mutation.

Kaposiform hemangioendothelioma with distant lymphangiomatosis without an association to Kasabach-Merritt-Syndrome in a female adult!

Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular tumor which usually occurs in infants. Clinically it appears as ill-defined red to purple indurated plaque. KHE is commonly associated with Kasabach-Merritt syndrome (KMS) and lymphangiomatosis.

CD7(-) T cells are late memory cells generated from CD7(+) T cells.

CD7(-) T cells constitute a distinct subset within the CD4(+) and CD8(+) T cell populations; their developmental and functional relationship to the majority of CD7(+) T cells, however, remained so far unresolved. We here elucidate that CD7(-) cells represent aging T cells in late memory cell development characterized by a high activation threshold, low effector capacities, and high sensitivity to activation-induced cell death (AICD). In this regard, CD7(-) T cells highly express killer cell lectin-like receptor G1 (KLRG-1), harbor telomeres of shorter lengths, a decreased telomerase expression per cell, and less amounts of T cell receptor rearrangement excision circles (TRECs) compared to CD7(+) cells.

Melanoma stem cells: targets for successful therapy?

Increasing evidence suggests that cancer is a disease in which the persistence of the tumor relies on a small population of tumor-initiating cells, the so called tumor stem cells (TSC). Only these cells are capable of self-renewal and thereby possess the ability for unlimited proliferation. One reason for the inability of conventional tumor treatments to achieve long-term cures seems to be that TSC are resistant to many therapeutic approaches.

Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2D.

The proinflammatory cytokine macrophage migration inhibitory factor (MIF) stimulates tumor cell proliferation, migration, and metastasis; promotes tumor angiogenesis; suppresses p53-mediated apoptosis; and inhibits antitumor immunity by largely unknown mechanisms. We here describe an overexpression of MIF in ovarian cancer that correlates with malignancy and the presence of ascites. Functionally, we find that MIF may contribute to the immune escape of ovarian carcinoma by transcriptionally down-regulating NKG2D in vitro and in vivo which impairs NK cell cytotoxicity toward tumor cells.