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Background Four epidemiologic forms of Kaposi's sarcoma have been described, all of which are associated with the human herpesvirus-8. In western countries, human herpesvirus-8 is more prevalent in homosexual men than in the general population, and anecdotal cases of Kaposi's sarcoma in HIV-negative homosexual men have been reported. Patients and methods We included HIV-negative homosexual and bisexual male patients with histologically proven Kaposi's sarcoma in a retrospective study. Clinical data were collected using a standardized form. Risk factors for human herpesvirus-8 infection and for the development of Kaposi's sarcoma were systematically recorded. Results Between 1995 and 2007, 28 men met the defined inclusion criteria. Mean age at first symptoms of Kaposi's sarcoma was 53 years. Clinical presentation resembled classical Kaposi's sarcoma, with limited disease in most patients. No cellular or humoral immunodeficiency was observed. Serologic tests for human herpesvirus-8 (latent immunofluorescence assay) were positive in 88% of patients, and only two patients displayed human herpesvirus-8 viremia at the time of Kaposi's sarcoma diagnosis. Three patients developed lymphoproliferative disorders (Castleman disease, follicular lymphoma and Burkitt lymphoma). In this population, alpha-interferon was well tolerated and gave a complete response, but most patients require only local treatment, if any. Conclusion Kaposi's sarcoma may develop in homosexual or bisexual men without HIV infection. This type of Kaposi's sarcoma has clinical features in common with classical Kaposi's sarcoma but occurs in younger patients. Its prognosis is good, as Kaposi's sarcoma is generally limited, but clinicians should be aware of the association with lymphoproliferative diseases, which may affect prognosis.

Contains fulltext : 58490.pdf (Publisher’s version ) (Closed access) Ideal vaccines should be stable, safe, molecularly defined, and out-of-shelf reagents efficient at triggering effector and memory Ag-specific T cell-based immune responses. Dendritic cell-derived exosomes could be considered as novel peptide-based vaccines because exosomes harbor a discrete set of proteins, bear functional MHC class I and II molecules that can be loaded with synthetic peptides of choice, and are stable reagents that were safely used in pioneering phase I studies. However, we showed in part I that exosomes are efficient to promote primary MHC class I-restricted effector CD8(+) T cell responses only when transferred onto mature DC in vivo. In this work, we bring evidence that among the clinically available reagents, Toll-like receptor 3 and 9 ligands are elective adjuvants capable of triggering efficient MHC-restricted CD8(+) T cell responses when combined to exosomes. Exosome immunogenicity across species allowed to verify the efficacy of good manufactory procedures-manufactured human exosomes admixed with CpG oligonucleotides in prophylactic and therapeutic settings of melanoma in HLA-A2 transgenic mice. CpG adjuvants appear to be ideal adjuvants for exosome-based cancer vaccines.

Summary Background Exosomes derived from tumours are small vesicles released in vitro by tumour cell lines in culture supematants. To assess the role of these exosomes in vivo, we examined malignant effusions for their presence. We also investigated whether these exosomes could induce production of tumour-specific T cells when pulsed with dendritic cells. Methods We isolated exosomes by ultracentrifugation on sucrose and D 2 O gradients of 11 malignant effusions. We characterised exosomes with Western blot analyses, immunoelectron microscopy, and in-vitro stimulations of autologous T lymphocytes. Findings Malignant effusions accumulate high numbers of membrane vesicles that have a mean diameter of 80 nm (SD 30). These vesicles have antigen-presenting molecules (MHC class-I heat-shock proteins), tetraspanins (CD81), and tumour antigens (Her2/Neu, Mart1, TRP, gp100). These criteria, including their morphological characteristics, indicate the similarities between these vesicles and exosomes. Exosomes from patients with melanoma deliver Mart1 tumour antigens to dendritic cells derived from monocytes (MD-DCs) for cross presentation to clones of cytotoxic T lymphocytes specific to Mart1. In seven of nine patients with cancer, lymphocytes specific to the tumour could be efficiently expanded from peripheral blood cells by pulsing autologous MD-DCs with autologous ascitis exosomes. In one patient tested, we successfully expanded a restricted T-cell repertoire, which could not be recovered carcinomatosis nodules. Interpretation Exosomes derived from tumours accumulate in ascites from patients with cancer. Ascitis exosomes are a natural and new source of tumour-rejection antigens, opening up new avenues for immunisation against cancers.

To our knowledge, we report the first case of improvement of HIV-associated cutaneous CD8(+) pseudolymphoma with highly active antiretroviral therapy. This favors the hypothesis of a reactive cutaneous infiltration by HIV-specific cytotoxic T cells in this disease.

To evaluate the prognostic value of melanocytic differentiation antigens and angiogenesis biomarkers in sentinel lymph nodes (SLNs) with melanoma micrometastases.Prognostic study of an inception cohort.Academic research. Patients Between July 1, 1999, and July 31, 2002, all patients who had primary cutaneous or mucosal melanomas that have a Breslow depth of 1.5 mm or greater, ulceration, or Clark level IV or V, or had SLN biopsies.By the use of quantitative reverse transcription-polymerase chain reaction, the expression of the following was analyzed in SLNs: 2 melanocytic differentiation antigens (tyrosinase [P17646] and melanoma antigen recognized by T cells [MART-1; Q16655]) and genes involved in angiogenesis (VEGF [NM_001025366] and VEGFR2 [AF035121]), lymphangiogenesis (VEGFC [NM_005429], VEGFR3 [X68203], LYVE1 [NM_016164], and PROX1 [002763]), and invasion (uPA [NM_002658], PAI1 [NM_00602], and EMMPRIN [L10240]). Outcome measures were the association of these melanocytic differentiation antigens and angiogenesis biomarkers with clinicopathologic characteristics of patients, and an evaluation of the prognostic value for relapse-free survival and overall survival.Ninety-one patients were included, with a median follow-up period of 41 months. Micrometastases were present in 15% (14 of 91) of patients. Tyrosinase (P.001), MART-1 (P.001), vascular endothelial growth factor 121 (VEGF(121)) (P = .007), and PAI1 (P = .02) expression was significantly associated with micrometastasis. In univariate analysis, histologic findings and tyrosinase and MART-1 expression were significantly associated with relapse-free survival. Tyrosinase and MART-1 expression was associated with overall survival. A multiple Cox proportional hazards regression model identified negative histologic findings and tyrosinase expression that exceeded 27 copies/copy of TATA box-binding protein (third quartile) as significantly associated with an increased risk of relapse or death.Quantitative assessment of melanocytic differentiation antigens in SLNs, which has prognostic value, is more specific than qualitative assessment. Prognosis may be more effectively predicted by the combination of quantitative assessment of melanocytic differentiation antigens in SLNs with histologic assessment. A significant association was found between the presence of micrometastases and the expression of angiogenesis biomarkers.

Background Kaposi's sarcoma (KS), a virus-associated neoplasm, can be treated locally or systemically with interferon alfa. Therefore, imiquimod, an immune response modifier able to induce interferon-α secretion in situ, could prove a good local treatment for KS skin lesions. Objective We sought to determine the efficacy and safety of imiquimod 5% cream for the topical treatment of classic or endemic KS skin lesions in patients who are HIV negative. Methods We conducted a prospective, open-label, single center, phase II clinical trial. Imiquimod cream was applied under occlusion 3 times a week for 24 weeks. The main efficacy end points were the safety of topical imiquimod and the overall clinical response in patients evaluated on the basis of modified AIDS Clinical Trials Group criteria at 36 weeks. The statistical analysis was based on the intent-to-treat data set. Results Seventeen patients were enrolled. Eight (47%) presented objective overall clinical response (2 complete and 6 partial responses). Tumor progression was noted in 6 patients. The most frequent side effects were local itching and erythema, seen in 9 patients (53%). Limitations This was not a randomized placebo-controlled study and was restricted to a small number of patients. Conclusion Topical imiquimod 5% cream had antitumor activity in about half the patients with classic and endemic KS and was generally well tolerated.

Dendritic cells (DC) are unique antigen-presenting cells capable of triggering NK cell effector functions and priming naive T cells in vivo. Microbial stimulation induces early IL-2 production by mouse DC. Previous reports demonstrated that IL-2 is enriched at the site of DC/T cell interaction and promotes allogeneic T cell proliferation. However, the direct role of DC-derived IL-2 in the differentiation of cytotoxic T lymphocytes and in NK cell triggering in vivo has not been investigated. Lipopolysaccharide (LPS) stimulation of mouse bone morrow-derived DC results in early IL-2 production unless IL-4 is introduced in DC cultures. Here we show that IL-2 produced by LPS-activated DC is dispensable for cognate T cell responses since IL-2 loss of function DC elicit OVA-specific Tc1 effector and memory lymphocytes in draining lymph nodes in a setting where ex vivo cultured DC do not transfer antigens to host DC. Moreover, adoptively transferred IL-2 loss of function DC maintain their capacity to trigger NK cell proliferation/recruitment in lymph nodes. Therefore, immediate inducible IL-2 production by DC following microbial infection might play a regulatory role at ports of entry rather than in secondary lymphoid organs.

International audience; Dendritic-cell-derived exosomes (DEX) secreted after dendritic cell loading with tumor peptides were found to mediate tumor rejection in mice. This observation prompted us to demonstrate that MHC class I/peptide complexes harbored onto exosomal membranes were capable of priming cytotoxic T cells and to mediate rejection of tumors expressing the relevant antigens. Moreover, DEX also promote NK cell activation in immunocompetent mice and NK cell-dependent antitumor effects. The first Phase I trial using DEX to immunize melanoma patients revealed the feasibility of DEX production in stage IV melanoma, their safety in long-term follow up and their bioactivity in vivo.

The biology of small vesicles (1–4) secreted from antigen-presenting cells (APCs) recently raised a great deal of interest with the demonstration of their potent immunostimulatory functions in tumor models (5,6). The origin of vesicle secretion was first described (7) in differentiating red blood cells where multivesicular bodies (MVBs) fused with plasma membrane in an exocytic manner. This exocytic pathway was later shown to occur in a wide variety of cell types such as B lymphocytes, mastocytes, immature dendritic cells (DCs), platelets, cytotoxic T lymphocytes (CTLs), fibroblasts, epithelial cells, and tumor cells (6,8–15). Vesicles exocytosed from MVBs into the extracellular medium are referred to as “exosomes” and should not be confused with the more recently described “ribonuclease complex” also named exosome.

Exosomes are 60 to 90 nm membrane vesicles originating from late endosomes and secreted from most hematopoietic and epithelial cells in vitro. B cell derived-exosome antigenicity was first reported in 1996 in MHC class II restricted CD4+ T lymphocytes. In 1998, we reported that dendritic cell derived-exosomes are immunogenic in mice leading to tumor rejection. These findings have renewed the interest in exosomes. The current challenge consists in understanding the mechanisms and the physiological relevance of exosomes that could contribute to the design of the optimal exosome based-vaccination. Here, we will focus on the biological features pertaining to dendritic cell- and tumor cell derived-exosomes and will discuss their potential clinical implementation.

Exosomes are small membrane vesicles originating from late endosomes and secreted by hematopoietic and epithelial cells in culture. Exosome proteic and lipid composition is unique and might shed some light into exosome biogenesis and function. Exosomes secreted from professional antigen-presenting cells (i.e., B lymphocytes and dendritic cells) are enriched in MHC class I and II complexes, costimulatory molecules, and hsp70-90 chaperones, and have therefore been more extensively studied for their immunomodulatory capacities in vitro and in vivo. This review will present the main biological features pertaining to tumor or DC-derived exosomes, will emphasize their immunostimulatory function, and will discuss their implementation in cancer immunotherapy.

Exosomes are small vesicles released by a broad array of hematopoietic cells. Previous studies showed that exosomes released by antigen loaded dendritic cells induce immune-mediated anti-tumor response in mice. Here, we will describe the biochemical properties of tumor-derived exosomes and, their pre-clinical activity as cancer vaccines.

Current immunization protocols in cancer patients involve CTL-defined tumor peptides. Mature dendritic cells (DC) are the most potent APCs for the priming of naive CD8+ T cells, eventually leading to tumor eradication. Because DC can secrete MHC class I-bearing exosomes, we addressed whether exosomes pulsed with synthetic peptides could subserve the DC function consisting in MHC class I-restricted, peptide-specific CTL priming in vitro and in vivo. The priming of CTL restricted by HLA-A2 molecules and specific for melanoma peptides was performed: 1) using in vitro stimulations of total blood lymphocytes with autologous DC pulsed with GMP-manufactured autologous exosomes in a series of normal volunteers; 2) in HLA-A2 transgenic mice (HHD2) using exosomes harboring functional HLA-A2/Mart1 peptide complexes. In this study, we show that: 1) DC release abundant MHC class I/peptide complexes transferred within exosomes to other naive DC for efficient CD8+ T cell priming in vitro; 2) exosomes require nature’s adjuvants (mature DC) to efficiently promote the differentiation of melanoma-specific effector T lymphocytes producing IFN-γ (Tc1) effector lymphocytes in HLA-A2 transgenic mice (HHD2). These data imply that exosomes might be a transfer mechanism of functional MHC class I/peptide complexes to DC for efficient CTL activation in vivo.