Human leukocyte antigen-G and cancer immunoediting

Immunosurveillance is an extrinsic mechanism of cancer suppression that eliminates nascent tumors. However, the selection imposed by immunosurveillance can drive tumor evolution and the emergence of clinically apparent neoplasms. Mechanisms of immune escape acquired by less immunogenic variants during this process, termed immunoediting, may contribute significantly to malignant progression. In this review, we summarize the evidence that up-regulation of the nonclassic human leukocyte antigen (HLA) class I molecule HLA-G in tumor cells plays an important role in cancer and immune escape

Baseline staging of melanoma with unknown primary site: the value of serum s100 protein and positron emission tomography

BACKGROUND: Baseline staging is important in all melanoma types, including melanoma with unknown primary site (MUP). Staging includes different examination strategies, each with different accuracy. OBJECTIVE: To determine the value of serum S100 protein levels and positron emission tomography (PET) in the baseline staging of MUP. METHODS: Twenty patients with MUP were evaluable for the analysis between 1996 and 2007 with both S100 assessment and PET performed for baseline staging. RESULTS: Serum S100 was elevated in 7 patients (35%). The PET scan detected the metastases in 6 of 7 patients with elevated serum S100 protein showing a strong correlation (p = 0.005). Patients with metastases had significantly higher serum S100 levels (p = 0.01) than the ones without. Serum S100 protein was shown to be discriminative between patients with and without metastases (receiver-operating characteristic, p = 0.012) with 75% sensitivity and 92% specificity. CONCLUSION: Serum S100 protein appears to be a sensitive as well as specific marker to detect metastases. We therefore might recommend serum S100 assessment to be included in the baseline staging of MUP

Cutaneous lymphoma, leukemia and related disorders

Mycosis fungoides (MF) is a general indolent peripheral T-cell lymphoma initially and preferentially present in the skin and showing distinct clinical, histological (except in early stages), immunophenotypical, and genotypical features. It is the most common cutaneous lymphoma [75, 100], characterized by the sequential appearance of patches, developing into plaques and finally into tumors, which tend to ulcerate

Evaluation of lymphangiogenic markers in Sézary syndrome

Sézary syndrome (SS) is regarded as a leukemic, aggressive subtype of cutaneous T-cell lymphoma (CTCL) characterized by the accumulation of malignant T-cells in the skin, as well as by blood and lymph node involvement. To date there have been no data on the extent of lymphangiogenesis in SS or erythrodermic mycosis fungoides (eMF). Lymphangiogenesis represents the de novo formation of lymphatic vasculature and has been associated with the occurrence of metastatic disease and poor prognosis. In this study we investigated lymphangiogenesis in skin biopsies from patients with SS and eMF. The expression of VEGFR-3 was significantly higher in patients with SS (p = 0.0285) as compared to patients with eMF. LYVE-1, podoplanin (PDPN), and VEGF-C stainings showed a similar tendency. The number of PDPN-expressing lymphatic vessels (p = 0.025) as well as CD31-positive blood vessels (p = 0.0065) correlated with disease progression in patients with SS. We show for the first time a non-vascular pattern of VEGF-C and VEGFR-3, i.e. their epidermal expression in erythrodermic CTCLs, suggesting their role in lymphocyte trafficking to the skin

HLA-G expression in basal cell carcinomas of the skin recurring after radiotherapy

Basal cell carcinoma (BCC) of the skin represents the most common malignancy in the fair-skinned population worldwide. HLA-G is one of the molecules implicated in immunotolerance. To investigate the role of HLA-G in recurring BCCs, we constructed a tissue microarray containing 38 primary BCCs that underwent radiotherapy and 14 secondary BCCs recurring on the primary site after radiotherapy, and evaluated the HLA-G protein expression by immunohistochemistry. The HLA-G protein was most frequently expressed in aggressive sclerosing BCCs. Nodular BCC demonstrated the strongest HLA-G expression. Interestingly, tumor infiltrating mononuclear cells (TIMC) expressed the HLA-G molecule in BCCs that showed no recurrence. After comparing primary BCCs and BCCs relapsed after radiotherapy, we observed decreased HLA-G expression on tumor cells and the loss of HLA-G expression on TIMC in relapsed BCCs. After radiotherapy, immunobiology of BCC may change resulting in the down-regulation of HLA-G expression on tumor and on tumor-infiltrating cells

An exploratory study of systemic administration of the toll-like receptor-7 agonist 852A in patients with refractory metastatic melanoma

PURPOSE: A topical Toll-like receptor 7 (TLR7) agonist induces regression of cutaneous melanocytic neoplasms. We explored antitumor activity of a systemically administered TLR7 agonist, 852A, in patients with metastatic melanoma. EXPERIMENTAL DESIGN: We undertook a phase II, multicenter, open-label study in patients with chemotherapy-refractory metastatic melanoma. Patients received i.v. 852A, starting at 0.6 mg/m(2) and increasing to 0.9 mg/m(2) based on tolerance, thrice per week for 12 weeks. Clinical response was determined by Response Evaluation Criteria in Solid Tumors. Immune effects of 852A were monitored by measuring serum type I IFN and IP-10 together with assessment of immune cell markers in peripheral blood. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the initial 12-week treatment cycle, with two discontinuing for adverse events considered to be possibly related to study drug. Four (19%) patients had disease stabilization for >100 days. One patient had a partial remission after two treatment cycles, but progressed during the third. Dose-limiting toxicity was observed in two patients. Serum type I IFN and IP-10 increased in most patients on 852A administration. Serum type I IFN increases were greater after dosing with 852A 0.9 mg/m(2) than after 0.6 mg/m(2) (P = 0.009). The maximal increase in IP-10 compared with baseline correlated with the maximal increase in type I IFN (P = 0.003). In the eight patients with immune cell marker data, CD86 expression on monocytes increased significantly post-first dose (P = 0.007). CONCLUSION: Intravenous 852A was well tolerated and induced systemic immune activation that eventually resulted in prolonged disease stabilization in some patients with stage IV metastatic melanoma who had failed chemotherapy