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ABSTRACT: The identification of novel compounds modulating the expression/activity of molecular targets downstream to BCR-ABL could be a new approach in the treatment of chronic myeloid leukemias (CMLs) resistant to imatinib or other BCR-ABL-targeted molecules. Recently, we synthesized a new class of substituted 2-(3,4,5-trimethoxybenzoyl)-2-N,N-dimethylamino-benzo[b]furans, and among these 3-iodoacetylamino-6-methoxybenzofuran-2-yl(3,5-trimethoxyphenyl)methanone (TR120) showed marked cytotoxic activity in BCR-ABL-expressing cells. Interestingly, TR120 was more potent than imatinib in cell growth inhibition and apoptosis induction in both BCR-ABL-expressing K562 and KCL22 cells. Moreover, it showed antitumor activity in imatinib-resistant K562-R and KCL22-R cells at concentrations similar to those active in the respective sensitive cells. Further, TR120 induced a marked decrease in signal transducer and activator of transcription 5 (STAT5) expression in K562 cells. Consistent with this effect, it determined a block of cells in the G0-G1 phase of the cell cycle, a decrease in the level of cyclin D1, and a reduction in Bcl-xL expression; however, it did not cause modifications in the Bcl-2 level. Of interest, TR120 had synergistic effects when used in combination with imatinib in both sensitive and resistant cells. Considering that STAT5 is a BCR-ABL molecular target that plays a key role in the pathogenesis of CML as well as in BCR-ABL-mediated resistance to apoptosis, TR120 could potentially be a useful novel agent in the treatment of imatinib-resistant CML.
Anti-cancer drugs 01/2013; · 2.23 Impact Factor
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Rossana Tallerico,
Matilde Todaro,
Simone Di Franco,
Cristina Maccalli,
Cinzia Garofalo,
Rosa Sottile,
Camillo Palmieri,
Luca Tirinato,
Pradeepa N Pangigadde,
Rosanna La Rocca,
Ofer Mandelboim,
Giorgio Stassi,
Enzo Di Fabrizio,
Giorgio Parmiani,
Alessandro Moretta, Francesco Dieli,
Klas Kärre,
Ennio Carbone
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ABSTRACT: Tumor cell populations have been recently proposed to be composed of two compartments: tumor-initiating cells characterized by a slow and asymmetrical growth, and the "differentiated" cancer cells with a fast and symmetrical growth. Cancer stem cells or cancer-initiating cells (CICs) play a crucial role in tumor recurrence. The resistance of CICs to drugs and irradiation often allows them to survive traditional therapy. NK cells are potent cytotoxic lymphocytes that can recognize tumor cells. In this study, we have analyzed the NK cell recognition of tumor target cells derived from the two cancer cell compartments of colon adenocarcinoma lesions. Our data demonstrate that freshly purified allogeneic NK cells can recognize and kill colorectal carcinoma-derived CICs whereas the non-CIC counterpart of the tumors (differentiated tumor cells), either autologous or allogeneic, is less susceptible to NK cells. This difference in the NK cell susceptibility correlates with higher expression on CICs of ligands for NKp30 and NKp44 in the natural cytotoxicity receptor (NCR) group of activating NK receptors. In contrast, CICs express lower levels of MHC class I, known to inhibit NK recognition, on their surface than do the "differentiated" tumor cells. These data have been validated by confocal microscopy where NCR ligands and MHC class I molecule membrane distribution have been analyzed. Moreover, NK cell receptor blockade in cytotoxicity assays demonstrates that NCRs play a major role in the recognition of CIC targets. This study strengthens the idea that biology-based therapy harnessing NK cells could be an attractive opportunity in solid tumors.
The Journal of Immunology 01/2013; · 5.79 Impact Factor
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ABSTRACT: Phenotypic and functional heterogeneity are the hallmarks of effector and memory T cells. Upon antigen stimulation, γδ T cells differentiate into two major types of memory T cells: central memory cells, which patrol the blood and secondary lymphoid organs, and effector memory cells, which migrate to peripheral tissues. γδ T cells display in vitro a certain degree of plasticity in their function that is reminiscent of that which is observed in conventional CD4 T cells. Similar to CD4 T cells, in which a plethora of specialized subsets affect the host response, γδ T cells may readily and rapidly assume distinct Th1-, Th2-, Th17-, T(FH) and T regulatory-like effector functions, suggesting that they profoundly influence cell-mediated and humoral immune responses. In addition to differences in cytokine repertoire, γδ T cells exhibit diversity in homing, such as migration to lymph node follicles, to help B cells versus migration to inflamed tissues. Here, we review our current understanding of γδ T-cell lineage heterogeneity and flexibility, with an emphasis on the human system, and propose a classification of effector γδ T cells based on distinct functional phenotypes.Cellular & Molecular Immunology advance online publication, 22 October 2012; doi:10.1038/cmi.2012.42.
Cellular & molecular immunology 10/2012; · 2.99 Impact Factor
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Emanuela Greco,
Gianluca Quintiliani,
Marilina B Santucci,
Annalucia Serafino,
Anna Rita Ciccaglione,
Cinzia Marcantonio,
Massimiliano Papi,
Giuseppe Maulucci,
Giovanni Delogu,
Angelo Martino, [......],
Alfonso Altieri,
Mario Alma,
Nadia Caccamo,
Diana Di Liberto,
Marco De Spirito,
Nigel D Savage,
Roberto Nisini, Francesco Dieli,
Tom H Ottenhoff,
Maurizio Fraziano
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ABSTRACT: We have generated unique asymmetric liposomes with phosphatidylserine (PS) distributed at the outer membrane surface to resemble apoptotic bodies and phosphatidic acid (PA) at the inner layer as a strategy to enhance innate antimycobacterial activity in phagocytes while limiting the inflammatory response. Results show that these apoptotic body-like liposomes carrying PA (ABL/PA) (i) are more efficiently internalized by human macrophages than by nonprofessional phagocytes, (ii) induce cytosolic Ca(2+) influx, (iii) promote Ca(2+)-dependent maturation of phagolysosomes containing Mycobacterium tuberculosis (MTB), (iv) induce Ca(2+)-dependent reactive oxygen species (ROS) production, (v) inhibit intracellular mycobacterial growth in differentiated THP-1 cells as well as in type-1 and -2 human macrophages, and (vi) down-regulate tumor necrosis factor (TNF)-α, interleukin (IL)-12, IL-1β, IL-18, and IL-23 and up-regulate transforming growth factor (TGF)-β without altering IL-10, IL-27, and IL-6 mRNA expression. Also, ABL/PA promoted intracellular killing of M. tuberculosis in bronchoalveolar lavage cells from patients with active pulmonary tuberculosis. Furthermore, the treatment of MTB-infected mice with ABL/PA, in combination or not with isoniazid (INH), dramatically reduced lung and, to a lesser extent, liver and spleen mycobacterial loads, with a concomitant 10-fold reduction of serum TNF-α, IL-1β, and IFN-γ compared with that in untreated mice. Altogether, these results suggest that apoptotic body-like liposomes may be used as a Janus-faced immunotherapeutic platform to deliver polar secondary lipid messengers, such as PA, into phagocytes to improve and recover phagolysosome biogenesis and pathogen killing while limiting the inflammatory response.
Proceedings of the National Academy of Sciences 04/2012; 109(21):E1360-8. · 9.68 Impact Factor
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ABSTRACT: The potent anti-tumor activities of γδ T cells, their ability to produce pro-inflammatory cytokines, and their strong cytolytic
activity have prompted the development of protocols in which γδ agonists or ex vivo-expanded γδ cells are administered to
tumor patients. γδ T cells can be selectively activated by either synthetic phosphoantigens or by drugs that enhance their
accumulation into stressed cells as aminobisphosphonates, thus offering new avenues for the development of γδ T cell-based
immunotherapies. The recent development of small drugs selectively activating Vγ9Vδ2 T lymphocytes, which upregulate the endogenous
phosphoantigens, has enabled the investigators to design the experimental approaches of cancer immunotherapies; several ongoing
phase I and II clinical trials are focused on the role of the direct bioactivity of drugs and of adoptive cell therapies involving
phosphoantigen- or aminobisphosphonate-activated Vγ9Vδ2 T lymphocytes in humans. In this review, we focus on the recent advances
in the activation/expansion of γδ T cells in vitro and in vivo that may represent a promising target for the design of novel
and highly innovative immunotherapy in patients with hematologic malignancies.
KeywordsVγ9Vδ2 T cells-Hematologic malignancies-Immunotherapy-Cytokines-Cytotoxicity
Oncology Reviews 04/2012; 4(4):211-218.
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ABSTRACT: INTRODUCTION: Recent evidence based on cancer stem cell (CSC) models, is boosting the progress of translational research and providing relevant clinical implications in many tumour types, including colorectal cancer. The current failure of standard therapies is attributed to a small fraction of the primary cell population with stem-like characteristics, such as self-renewal and differentiation. Identification of CSCs is based on two different criteria of selection: stemness-selective conditions and direct isolation based on putative stem cell markers expression. CD133, a transmembrane glycoprotein, was associated with tumor-initiating cells derived from several histological variants of tumors, including colon. AREAS COVERED: In this review the current understandings about CD133 as putative marker of tumour-initiating cells in colorectal cancer (CRC) is described. The focus of the discussion is on the need for additional markers to better identify the cell population able to recapitulate the parental tumor in immunocompromised mice. EXPERT OPINION: Identification and characterization of CSCs represents a relevant issue to define innovative therapeutic approaches, overcoming the emergence of cancer cell clones capable of evading standard therapy.
Expert opinion on therapeutic targets 03/2012; 16(3):259-67. · 3.72 Impact Factor
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02/2012; , ISBN: 978-953-307-942-4
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ABSTRACT: In chronic inflammatory disorders, interleukin (IL)-22 may act either as a protective or as a pro-inflammatory cytokine. At mucosal sites, IL-22 is mainly produced by CD4(+) T cells and by a subset of mucosal natural killer (NK) cells expressing the receptor NKp44 (NKp44(+) NK cells). The aim of this study was to investigate the IL-22 expression in the salivary glands of patients with primary Sjögren's syndrome (pSS).
Minor salivary gland biopsies were obtained from 19 patients with pSS and 16 with non-specific chronic sialoadenitis. Quantitative gene expression analysis by TaqMan real-time PCR and immunohistochemistry for IL-17, IL-22, IL-23 and STAT3 (signal transducer and activator of transcription) was performed on salivary glands from patients and controls. The cellular sources of IL-22 among infiltrating inflammatory cells were also determined by fluorescence-activated cell sorting analysis and immunohistochemistry.
IL-22, IL-23 and IL-17 were significantly increased at both protein and mRNA levels in the inflamed salivary glands of patients with pSS. STAT3 mRNA and the tyrosine phosphorylated corresponding protein were also significantly increased in pSS. Th17 and NKp44(+) NK cells were the major cellular sources of IL-22 in patients with pSS.
Our results suggest that, together with IL-17 and IL-23, IL-22 may play a pro-inflammatory role in the pathogenesis of pSS.
Annals of the rheumatic diseases 02/2012; 71(2):295-301. · 8.11 Impact Factor
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ABSTRACT: Zoonoses include a broad range of diseases, that are becoming of great interest, due to the climate changing, that cause the adaptation of vectors to new niches and environments. Host immune responses play a crucial role in determining the outcome of infections, as documented by expansion of antigen-specific T cells during several zoonotic infections. Thus, understanding of the contribution of antigen-specific T-cell subsets in the host immune response is a powerful tool to evaluate the different immunological mechanisms involved in zoonotic infections and for the development of effective vaccines. In this paper we discuss the role of T cells in some eukaryotic and prokaryotic infectious models.
Clinical and Developmental Immunology 01/2012; 2012:768789. · 1.84 Impact Factor
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ABSTRACT: In this paper we focus our attention on the role of two families of receptors, Toll-like receptors (TLR) and decoy receptors (DcR) involved in the generation of systemic lupus erythematosus (SLE) and lupus-like syndromes in human and mouse models. To date, these molecules were described in several autoimmune disorders such as rheumatoid arthritis, antiphospholipids syndrome, bowel inflammation, and SLE. Here, we summarize the findings of recent investigations on TLR and DcR and their role in the immunopathogenesis of the SLE.
Clinical and Developmental Immunology 01/2012; 2012:135932. · 1.84 Impact Factor
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ABSTRACT: Vγ9Vδ2 T lymphocytes recognize nonpeptidic antigens without presentation by MHC molecules and display pleiotropic features. Here we report that coculture of Vγ9Vδ2 cells with phosphoantigen and IL-21 leads to selective expression of the transcription repressor Bcl-6 and polarization toward a lymphocyte subset displaying features of follicular B-helper T (T(FH)) cells. T(FH)-like Vγ9Vδ2 cells have a predominant central memory (CD27(+)CD45RA(-)) phenotype and express ICOS, CD40L and CXCR5. Upon antigen activation, they secrete IL-4, IL-10 and CXCL13, and provide B-cell help for antibody production in vitro. Our findings delineate a subset of human Vγ9Vδ2 lymphocytes, which, upon interaction with IL-21-producing CD4 T(FH) cells and B cells in secondary lymphoid organs, is implicated in the production of high affinity antibodies against microbial pathogens.
PLoS ONE 01/2012; 7(7):e41940. · 4.09 Impact Factor
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Adriana Cordova,
Francesca Toia,
Carmela La Mendola,
Valentina Orlando,
Serena Meraviglia,
Gaetana Rinaldi,
Matilde Todaro,
Giuseppe Cicero,
Leonardo Zichichi,
Paolo Li Donni,
Nadia Caccamo,
Giorgio Stassi, Francesco Dieli,
Francesco Moschella
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ABSTRACT: T lymphocytes are often induced naturally in melanoma patients and infiltrate tumors. Given that γδ T cells mediate antigen-specific killing of tumor cells, we studied the representation and the in vitro cytokine production and cytotoxic activity of tumor infiltrating γδ T cells from 74 patients with primary melanoma. We found that γδ T cells represent the major lymphocyte population infiltrating melanoma, and both Vδ1(+) and Vδ2(+) cells are involved. The majority of melanoma-infiltrating γδ cells showed effector memory and terminally-differentiated phenotypes and, accordingly, polyclonal γδ T cell lines obtained from tumor-infiltrating immune cells produced IFN-γ and TNF-α and were capable of killing melanoma cell lines in vitro. The cytotoxic capability of Vδ2 cell lines was further improved by pre-treatment of tumor target cells with zoledronate. Moreover, higher rate of γδ T cells isolation and percentages of Vδ2 cells correlate with early stage of development of melanoma and absence of metastasis. Altogether, our results suggest that a natural immune response mediated by γδ T lymphocytes may contribute to the immunosurveillance of melanoma.
PLoS ONE 01/2012; 7(11):e49878. · 4.09 Impact Factor
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Paola Di Carlo,
Alessandra Casuccio,
Amelia Romano,
Daria Spicola,
Lucina Titone,
Nadia Caccamo, Francesco Dieli,
Caterina Mammina,
Elisabetta Pace,
Mark Gjomarkaj,
Mario Melis,
Manlio Tolomeo
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ABSTRACT: Studies of the apoptosis mechanisms involved in the pathogenesis of tuberculosis have suggested that Mycobacterium tuberculosis can actively interfere with the apoptosis of infected cells. In vivo studies have been performed in adult populations but have not focused on this process in children. In the present study, we analyzed spontaneous T lymphocyte (PBT) apoptosis in the peripheral blood of children with central nervous system tuberculosis (CNS TB), before and after chemotherapy, and compared the results with healthy controls.
A case-control study was conducted from January 2002 to June 2009. It included 18 children with CNS TB and 17 healthy controls. Spontaneous apoptosis of PBTs, including CD4+, CD8+ and CD8+/CD28+ T cells, was evaluated after 24 and 72 h of culture in complete medium, using the Annexin V detection test. Analysis was conducted before and after chemotherapy, and expression of the apoptotic markers CD95 (Fas) and Fas ligand (FasL) was evaluated.
Higher percentages of apoptotic T cells and CD4 lymphocytes were isolated from children with acute phase CNS TB than from children in the control group (p < 0.05). This difference significantly decreased after 60 days of specific treatment. In children with CNS TB, high levels of Fas ligand expression were detected in lymphocyte populations, associated with a high percentage of Fas positive cells, before and after treatment. In contrast to the CD4+ apoptosis profile, we did not find any significant difference in total CD8+ cell apoptosis between children with acute phase disease and the control group. However, the percentage of apoptotic CD8+/CD28+ T cells was significantly higher in the children with acute phase disease than in the healthy controls.
Our findings indicate that CNS TB in pediatric patients increases the sensitivity of CD4 and CD8+/CD28+ T cells to apoptosis, suggesting a hypoergic status of this infection. This could play a key role in the immunopathogenesis of this complicated form of TB. Interestingly, specific chemotherapy is able to normalize both apoptosis sensitivity and T-cell activation.
BMC Pediatrics 11/2011; 11:108. · 1.88 Impact Factor
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ABSTRACT: In healthy adults, the major peripheral blood γδ T-cell subset expresses the Vγ9Vδ2 TCR and displays pleiotropic features. Here we report that coculture of naive Vγ9Vδ2 T cells with phosphoantigens and a cocktail of cytokines (IL-1-β, TGF-β, IL-6, and IL-23), leads to selective expression of the transcription factor RORγt and polarization toward IL-17 production. IL-17(+) Vγ9Vδ2 T cells express the chemokine receptor CCR6 and produce IL-17 but neither IL-22 nor IFN-γ; they have a predominant terminally differentiated (CD27(-)CD45RA(+)) phenotype and express granzyme B, TRAIL, FasL, and CD161. On antigen activation, IL-17(+) Vγ9Vδ2 T cells rapidly induce CXCL8-mediated migration and phagocytosis of neutrophils and IL-17-dependent production of β-defensin by epithelial cells, indicating that they may be involved in host immune responses against infectious microorganisms. Accordingly, an increased percentage of IL-17(+) Vγ9Vδ2 lymphocytes is detected in the peripheral blood and at the site of disease in children with bacterial meningitis, and this pattern was reversed after successful antibacterial therapy. Most notably, the phenotype of IL-17(+) Vγ9Vδ2 T cells in children with meningitis matches that of in vitro differentiated IL-17(+) Vγ9Vδ2 T cells. Our findings delineate a previously unknown subset of human IL-17(+) Vγ9Vδ2 T lymphocytes implicated in the pathophysiology of inflammatory responses during bacterial infections.
Blood 04/2011; 118(1):129-38. · 9.90 Impact Factor
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ABSTRACT: In the last 10 years, cancer stem cells have interested the scientific community because this small tumorigenic population is also associated with tumor progression in human patients and specific targeting of cancer stem cells could be a strategy to eradicate cancers currently resistant to conventional therapy. Clinical studies have recently demonstrated that adding immune therapy to chemotherapy has survival benefits in comparison with chemotherapy alone that can sensitize tumors to immune cell-mediated killing (e.g., increasing sensitivity of tumor cells to subsequent cytotoxicity by T cells via upregulation of death receptors DR5 and Fas). However, loss of MHC molecules is often observed in cancer cells, rendering tumor cells resistant to CD8 T-cell-mediated cytotoxicity. For this reason, we review the role of other T-cell subsets, such as γδ T and NK cells that are able to efficiently recognize and kill tumor cells and that could be used in passive or active immunotherapy in cancer stem cell eradication.
Immunotherapy 01/2011; 3(1):97-106. · 1.85 Impact Factor
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Sheila T Tang,
Krista E van Meijgaarden,
Nadia Caccamo,
Giuliana Guggino,
Michèl R Klein,
Pascale van Weeren,
Fatima Kazi,
Anette Stryhn,
Alexander Zaigler,
Ugur Sahin,
Søren Buus, Francesco Dieli,
Ole Lund,
Tom H M Ottenhoff
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ABSTRACT: Although CD8(+) T cells help control Mycobacterium tuberculosis infection, their M. tuberculosis Ag repertoire, in vivo frequency, and functionality in human tuberculosis (TB) remains largely undefined. We have performed genome-based bioinformatics searches to identify new M. tuberculosis epitopes presented by major HLA class I supertypes A2, A3, and B7 (covering 80% of the human population). A total of 432 M. tuberculosis peptides predicted to bind to HLA-A*0201, HLA-A*0301, and HLA-B*0702 (representing the above supertypes) were synthesized and HLA-binding affinities determined. Peptide-specific CD8(+) T cell proliferation assays (CFSE dilution) in 41 M. tuberculosis-responsive donors identified 70 new M. tuberculosis epitopes. Using HLA/peptide tetramers for the 18 most prominently recognized HLA-A*0201-binding M. tuberculosis peptides, recognition by cured TB patients' CD8(+) T cells was validated for all 18 epitopes. Intracellular cytokine staining for IFN-γ, IL-2, and TNF-α revealed mono-, dual-, as well as triple-positive CD8(+) T cells, indicating these M. tuberculosis peptide-specific CD8(+) T cells were (poly)functional. Moreover, these T cells were primed during natural infection, because they were absent from M. tuberculosis-noninfected individuals. Control CMV peptide/HLA-A*0201 tetramers stained CD8(+) T cells in M. tuberculosis-infected and noninfected individuals equally, whereas Ebola peptide/HLA-A*0201 tetramers were negative. In conclusion, the M. tuberculosis-epitope/Ag repertoire for human CD8(+) T cells is much broader than hitherto suspected, and the newly identified M. tuberculosis Ags are recognized by (poly)functional CD8(+) T cells during control of infection. These results impact on TB-vaccine design and biomarker identification.
The Journal of Immunology 01/2011; 186(2):1068-80. · 5.79 Impact Factor
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ABSTRACT: Protective immunity against mycobacterial infections such as Mycobacterium tuberculosis is mediated by interactions between specific T cells and activated antigen presenting cells. To date, many aspects of mycobacterial immunity have shown that innate cells could be the key elements that substantially may influence the subsequent adaptive host response. During the early phases of infection, innate lymphocyte subsets play a pivotal role in this context. Here we summarize the findings of recent investigations on γδ T lymphocytes and their role in tuberculosis immunity.
Clinical and Developmental Immunology 01/2011; 2011:587315. · 1.84 Impact Factor
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ABSTRACT: T cells have several innate cell-like features that allow their early activation following recognition of conserved stress-induced ligands. V9V2 T cells, the dominant subset of T cell in human peripheral blood, recognize phosphoantigens such as isopentenyl pyrophosphate generated in the mevalonate pathway. Upon activation, cells display strong cytotoxicity towards various hemopoietic and nonhemopoietic tumors. Synthetic compounds have been recently patented which efficiently activate cells in vitro and in vivo. In addition, the mevalonate pathway in mammalian cells can be manipulated by drugs such as aminobisphosphonates, giving rise to the development of new strategies in tumor immunotherapy. Thus, the recent developments in the discoveries of new molecules capable of activating these subsets of innate-like lymphocytes open new avenues for T cell based immunotherapy of tumors.
Recent Patents on Biomarkers. 01/2011; 100.
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ABSTRACT: Nowadays it is reported that, similarly to other solid tumors, colorectal cancer is sustained by a rare subset of cancer stem–like cells (CSCs), which survive conventional anticancer treatments, thanks to efficient mechanisms allowing escape from apoptosis, triggering tumor recurrence. To improve patient outcomes, conventional anticancer therapies have to be replaced with specific approaches targeting CSCs. In this review we provide strong support that BMP4 is an innovative therapeutic approach to prevent colon cancer growth increasing differentiation markers expression and apoptosis. Recent data suggest that in colorectal CSCs, protection from apoptosis is achieved by interleukin-4 (IL-4) autocrine production through upregulation of antiapoptotic mediators, including survivin. Consequently, IL-4 neutralization could deregulate survivin expression and localization inducing chemosensitivity of the colon CSCs pool.
Cancersit (V.S. 01/2011; 3.
