Chiara Castelli

Bio: Chiara Castelli is an academic researcher from University of Milan. The author has contributed to research in topics: Antigen & Cytotoxic T cell. The author has an hindex of 48, co-authored 130 publications receiving 11593 citations. Previous affiliations of Chiara Castelli include National Institutes of Health & Istituto Superiore di Sanità.

Phenotypic characterization of human colorectal cancer stem cells

Abstract: Recent observations indicate that, in several types of human cancer, only a phenotypic subset of cancer cells within each tumor is capable of initiating tumor growth. This functional subset of cancer cells is operationally defined as the “cancer stem cell” (CSC) subset. Here we developed a CSC model for the study of human colorectal cancer (CRC). Solid CRC tissues, either primary tissues collected from surgical specimens or xenografts established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, were disaggregated into single-cell suspensions and analyzed by flow cytometry. Surface markers that displayed intratumor heterogeneous expression among epithelial cancer cells were selected for cell sorting and tumorigenicity experiments. Individual phenotypic cancer cell subsets were purified, and their tumor-initiating properties were investigated by injection in NOD/SCID mice. Our observations indicate that, in six of six human CRC tested, the ability to engraft in vivo in immunodeficient mice was restricted to a minority subpopulation of epithelial cell adhesion molecule (EpCAM)high/CD44+ epithelial cells. Tumors originated from EpCAMhigh/CD44+ cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Analysis of the surface molecule repertoire of EpCAMhigh/CD44+ cells led to the identification of CD166 as an additional differentially expressed marker, useful for CSC isolation in three of three CRC tested. These results validate the stem cell working model in human CRC and provide a highly robust surface marker profile for CRC stem cell isolation.

A listing of human tumor antigens recognized by T cells.

Abstract: Complete list of abbreviations of tumor antigens 707-AP 707 alanine proline-AFP alpha (α)-fetoprotein-ART-4 adenocarcinoma antigen recognized by T cells 4 BAGE B antigen-β-catenin/m β-catenin/mutated-Bcr-abl breakpoint cluster region-Abelson - CAMEL CTL-recognized antigen on melanoma CAP-1 carcinoembryonic antigen peptide-1-CASP-8 caspase-8 CDC27m cell-division-cycle 27 mutated-CDK4/m cycline-dependent kinase 4 mutated-CEA carcino-embryonic antigen-CT cancer/testis (antigen)-Cyp-B cyclophilin B DAM differentiation antigen melanoma (the epitopes of DAM-6 and DAM-10 are equivalent, but the gene sequences are different; DAM-6 is also called MAGE-B2. and DAM-10 is also called MAGE-B1) ELF2M elongation factor 2 mutated ETV6-AML1 Ets variant gene 6/acute myeloid leukemia 1 gene ETS G250 glycoprotein 250 - GAGE G antigen GnT-V N-acetylglucosaminyltransferase V -Gp100 glycoprotein 100 kDa-HAGE helicose antigen-HER-2/neu human epidermal receptor-2/ neurological - HLA-A * 0201-R1701 arginine (R) to isoleucine (I) exchange at residue 170 of the α-helix of the α2-domain in the HLA-A2 gene HPV-E7 human papilloma virus E7 HSP70-2M heat shock protein 70-2 mutated HST-2 human signet ring tumor-2 hTERT or hTRT human telomerase reverse transcriptase-iCE intestinal carboxyl esterase KIAA0205 name of the gene as it appears in databases-LAGE L antigen LDLR/FUT low-density lipid receptor/GDP-L-fucose: β-D-galactosidase 2-α-L-fucosyltransferase MAGE melanoma antigen MART-1/Melan-A melanoma antigen recognized by T cells-1/melanoma antigen A MC1R melanocortin 1 receptor Myosin/m myosin mutated-MUC1 mucin 1-MUM-1, -2, -3 melanoma ubiquitous mutated 1, 2, 3 NA88-A NA cDNA clone of patient M88-NY-ESO-1 New York-esophagus 1 - P15 protein 15 p190 minor bcr-abl protein of 190 kDa ber-abl Pml/RARα promyelocytic leukaemia/retinoic acid receptor α-PRAME preferentially expressed antigen of melanoma PSA prostate-specific antigen-PSM prostate-specific membrane antigen-RAGE renal antigen RU1 or RU2 renal ubiquitous 1 or 2 SAGE sarcoma antigen SART-1 or SART-3 squamous antigen rejecting tumor 1 or 3-TEL/ AML1 translocation Ets-family leukemia/acute myeloid leukemia 1 TPI/m triosephosphate isomerase mutated TRP-1 tyrosinase related protein 1, or gp75 TRP-2 tyrosinase related protein 2 TRP-2/ INT2 TRP-2/intron 2 WT1 Wilms' tumor gene Abbreviations used ALL acute lymphoblastic leukemia AML acute myeloid leukemia-APL acute promyelocytic leukemia-CML chronic myelogenous leuke mia-CTL cytotoxic T lymphocytes-Ets E-26 transforming specific (family of transcription factors) H/N head and neck-MHC major histocompatibility complex-NSCLC non-small cell lung carcinoma-ORF open reading frame RCC renal cell carcinoma-SCC squamous cell carcinoma-TSTA tumor-specific transplantation antigens.

Induction of lymphocyte apoptosis by tumor cell secretion of FasL-bearing microvesicles.

Abstract: The hypothesis that FasL expression by tumor cells may impair the in vivo efficacy of antitumor immune responses, through a mechanism known as ‘Fas tumor counterattack,’ has been recently questioned, becoming the object of an intense debate based on conflicting results. Here we definitely show that FasL is indeed detectable in the cytoplasm of melanoma cells and its expression is confined to multivesicular bodies that contain melanosomes. In these structures FasL colocalizes with both melanosomal (i.e., gp100) and lysosomal (i.e., CD63) antigens. Isolated melanosomes express FasL, as detected by Western blot and cytofluorimetry, and they can exert Fas-mediated apoptosis in Jurkat cells. We additionally show that melanosome-containing multivesicular bodies degranulate extracellularly and release FasL-bearing microvesicles, that coexpress both gp100 and CD63 and retain their functional activity in triggering Fas-dependent apoptosis of lymphoid cells. Hence our data provide evidence for a novel mechanism potentially operating in Fas tumor counterattack through the secretion of subcellular particles expressing functional FasL. Such vesicles may form a sort of front line hindering lymphocytes and other immunocompetent cells from entering neoplastic lesions and exert their antitumor activity.

Identification of a New Subset of Myeloid Suppressor Cells in Peripheral Blood of Melanoma Patients With Modulation by a Granulocyte-Macrophage Colony-Stimulation Factor–Based Antitumor Vaccine

Abstract: Purpose Phenotypic and functional features of myeloid suppressor cells (MSC), which are known to serve as critical regulators of antitumor T-cell responses in tumor-bearing mice, are still poorly defined in human cancers. Here, we analyzed myeloid subsets with suppressive activity present in peripheral blood of metastatic melanoma patients and evaluated their modulation by a granulocyte-macrophage colony-stimulating factor (GM-CSF) –based antitumor vaccine. Patients and Methods Stage IV metastatic melanoma patients (n = 16) vaccinated with autologous tumor-derived heat shock protein peptide complex gp96 (HSPPC-96) and low-dose GM-CSF provided pre- and post-treatment whole blood specimens. Peripheral-blood mononuclear cells (PBMCs) were analyzed by flow cytometry, separated into cellular subsets, and used for in vitro proliferation assays. PBMCs from stage-matched metastatic melanoma patients (n = 12) treated with non–GM-CSF-based vaccines (ie, HSPPC-96 alone or interferon alfa/melanoma–derived peptides) o...

A listing of human tumor antigens recognized by T cells: March 2004 update

Abstract: The technological advances occurred in the last few years have led to a great increase in the number of tumor associated antigens (TAA) that are currently available for clinical applications. In this review we provide a comprehensive list of human tumor antigens as reported in the literature updated at Feburary 2004. The list includes all T cell-defined epitopes, while excluding analogs or artificially modified epitopes, as well as virus-encoded and antibodies-recognized antigens. TAAs are listed in alphabetical order along with the epitope sequence and the HLA allele which restricts recognition by T cells. Data on the tissue distribution of each antigen are also provided together with an extensive bibliography that allows a rapid search for any additional information may be needed on each single antigen or epitope. Overall, the updated list is a database tool for clinicians, scientists and students who have an interest in the field of tumor immunology and immunotherapy.

Myeloid-derived suppressor cells as regulators of the immune system.

Abstract: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that expand during cancer, inflammation and infection, and that have a remarkable ability to suppress T-cell responses. These cells constitute a unique component of the immune system that regulates immune responses in healthy individuals and in the context of various diseases. In this Review, we discuss the origin, mechanisms of expansion and suppressive functions of MDSCs, as well as the potential to target these cells for therapeutic benefit.

Pembrolizumab for the treatment of non-small cell lung cancer

Abstract: BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

Exosomes: composition, biogenesis and function

Abstract: Exosomes are small membrane vesicles of endocytic origin that are secreted by most cells in culture. Interest in exosomes has intensified after their recent description in antigen-presenting cells and the observation that they can stimulate immune responses in vivo. In the past few years, several groups have reported the secretion of exosomes by various cell types, and have discussed their potential biological functions. Here, we describe the physical properties that define exosomes as a specific population of secreted vesicles, we summarize their biological effects, particularly on the immune system, and we discuss the potential roles that secreted vesicles could have as intercellular messengers.

Photodynamic therapy of cancer: An update†‡

Abstract: Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment. CA Cancer J Clin 2011;61:250-281. V C

The immune contexture in human tumours: impact on clinical outcome

Abstract: Tumours grow within an intricate network of epithelial cells, vascular and lymphatic vessels, cytokines and chemokines, and infiltrating immune cells. Different types of infiltrating immune cells have different effects on tumour progression, which can vary according to cancer type. In this Opinion article we discuss how the context-specific nature of infiltrating immune cells can affect the prognosis of patients.